KR20110125247A - Peptides used in the treatment and/or care of skin, mucous membranes and/or scalp and their use in cosmetic or pharmaceutical compositions - Google Patents

Abstract

The present invention provides a peptide of formula 1, R ₁ -Wp-Xn-AA ₁ -AA ₂ -AA ₃ -AA ₄ -Ym-R ₂ , stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceutically acceptable Possible salts, and methods of making the same, the cosmetics or cosmetics containing the same, and peptides and cosmetics or pharmaceutical compositions used for the treatment and / or care of the skin, mucous membranes and / or scalp, diseases, disorders of the skin, mucous membranes and / or scalp And / or for use in the treatment, prevention and / or management of a disease.

Description

Peptides USED IN THE TREATMENT AND / OR CARE OF SKIN, MUCOUS MEMBRANES AND / OR SCALP AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS}

The present invention provides a peptide capable of inhibiting the elastase activity of the skin, mucous membranes and / or scalp and / or promoting collagen synthesis, and a cosmetic or pharmaceutical composition containing the peptide, and preferably an advantage of promoting collagen synthesis. Used to treat and / or manage the skin, mucous membranes and / or scalp thereby to treat, prevent and / or manage diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp resulting from elastase activity. It's about things.

The skin consists of two layers, the dermis and the epidermis. The epidermis is the outermost layer, consisting of keratinocytes, melanocytes and langerhans cells. The major cell population of the epidermis is composed of keratinocytes, which form a constantly regenerating stratum corneum. Its function is to protect the skin from foreign substances, whether physical or chemical. The dermis is located more internally and is attached to the epidermis through the basement membrane. The dermis is composed of fibroblasts, adipocytes and macrophages, and has many nerve endings that draw water by blood vessels and convey a sense of contact and temperature. In the dermis, as well as hair follicles, sweat glands, sebaceous glands, apocrine gland (apocrine gland) is located, its function is to maintain the integrity and elasticity of the skin. This property is provided by an extracellular matrix composed of proteins secreted by fibroblasts.

Proteins of the extracellular matrix (ECM) fall into two classes: glycosaminoglycans and fibrous proteins. Glycosaminoglycans (GAG) are unbranched chains resulting from the polymerization of aminosugar disaccharides. GAGs, due to their chemical properties and numerous negative charges, make ECMs resistant to compression by forming bulky structures that tend to attract large amounts of water. Fibrous proteins have structural and adhesive functions and consist mainly of two components, elastin and collagen, which are responsible for the mechanical properties of tissues such as kidney, compression, stretch and torsion resistance.

The elasticity and recovery properties of the ECM are due to the elastic fiber network. Structurally, the resilient fiber consists of an elastin core and a microfibril pod of about 10 nm in diameter surrounding it. Microfibrils consist of fibrillin and microfibrils-related glycoproteins (MAGP). The assembly of the resilient fibers takes place in a continuous manner, in which microfibrils appear first and then a framework in which elastin is deposited is formed. Elastin is a highly hydrophobic protein, composed of about 750 amino acid residues, produced from tropoelastin, a water soluble precursor secreted into the extracellular space by fibroblasts.

Tropoelastin molecules are synthesized in water-soluble form with a molecular weight of about 70 kDa, with alternating hydrophobic and crosslinked domains [Brown-Augsburger P., Tisdale C. Broekelmann T., Sloan C. and Mecham RP. (1995) “Identification of an elastin crosslinking domain that join three peptide chains.” J. Biol. Chem. 270: 17778-17783. The hydrophobic domain is a repetition of a peptide of 2 to 9 amino acids rich in proline, alanine, valine, leucine, isoleucine and glycine, especially rich in valine and glycine [Debelle L. and Tamburro A.M. (1999) "Elastin: molecular description and function" Int J. Biochem. Cell Biol. 31: 261-272. Interactions between hydrophobic domains are important for assembly and essential for the elasticity of molecules [Bellingham C.M., Woodhouse K.A., Robson P., Rothstein S.J. And Keeley F.W. (2001) "Self-aggregation of recombinantly expressed human elastin polypeptides" Biochim. Biophys. Acta. 1550: 6-19. The crosslinking domain of tropoelastin contains a lysine residue in the proline-rich region or the polyalanine region. Covalent cross-linking formation of desmosin by lysyl oxidase stabilizes polymerization and water-insoluble products [Csiszar K. (2001) "Lysyl oxidase: a novel multifunctional amine oxidase family) "Prog. Nucleic Acid Res. Mol. Biol. 70: 1-32], and only two oxidase lysyl proteins called LOX and LOXL can crosslink water-insoluble elastin [Borel A., Eichenberger D., Farjanel J. kessler E., Gleyzal C., Hulmes DJS , Sommer P and Font B. (2001) "Lysyl oxidase-like protein from bovine aorta" J. Biol. Chem. 276: 48944-48949. In addition, the translated tropoelastin sequences have negatively charged hydrophilic C-terminal domains that are highly conserved between species. The major post-translational change that affects these molecules is the hydroxylation of proline residues.

Elastogenesis (elastogenesis) is a process that induces the formation of functional elastin in the elastic fibers. This process begins with the synthesis of tropoelastin molecules in cells, where 67 kDa galactose lectins are bound to act as chaperons that prevent intracellular aggregation of tropoelastin molecules. This complex is secreted into the extracellular space, where galactose lectins interact with the microfibrils galactosuga, thereby lowering the affinity for tropoelastin and release locally. Whereas the 67 kDa galatose lectin can be recycled and resume its function, tropoelastin is micropied due to the interaction of the N-terminal domain of microfibrils-associated glycoprotein (MAGP) with the C-terminal domain of tropoelastin. It is deposited on the skeleton formed by the brill component. Once alignment is achieved, most of the lysine residues of troponin elastin is re-amination, and Cu ^{+ 2} - is oxidized to an aldehyde by the action of florisil dependent oxidase. Crosslinking occurs during the reaction of the aldehydes thus produced with themselves or with unchanged lysine, resulting in the tropoelastin chain becoming insoluble and the elastin network growing. Molecules belonging to the emiline and fiblin systems that are thought to be able to control the deposition of tropoelastin on microfibrils are found at the cell membrane-elastic fibers and at the elastin-microfibrils interface. There is currently no evidence that molecules other than fibrin are indispensable for the assembly of microfibrils [Kielty CM, Sherratt MJ and Shuttleworth CA (2002) "Elastic fibers" J. Cell. Sci. 115: 2817-2828. Mature elastin is a water-insoluble polymer of tropoelastin that is covalently bonded by crosslinking and has di-, tri- or tetra-functionality. Complexity is estimated to increase with time. Hydrophobic fragments are very fluid and have a great impact on the entropy of the system, and also affect the entropy of the system of water transfer that hydrates the polymer in vivo. [Debelle L. and Tamburro AM (1999) "Elastin: Molecular Description and Function ( Elastin: molecular description and function) "Int J. Biochem. Cell Biol. 31: 261-272.

 Elastic fibers are important for maintaining the elasticity of the skin, and also in other tissues and organs, such as the lungs or large blood vessel walls [Faury G. (2001) "Function-Structure Correlation of Elastic Arteries in Evolution: Microfibrils Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibers "Pathol. Biol. (Paris) 49: 310-325. Defects in the formation of elastic fibers, such as modification of genes encoding the different proteins that make up the elastic fibers, result in several diseases. Thus, modification of the fibrin-1 gene causes the Marfan Syndrome (associated with skeletal, eye and cardiovascular syndrome), and modification of the fibrin-2 gene is congenital contractile in addition to eye and skeletal syndrome. Resulting in congenital contractual arachnodactyly, and alteration of the elastin gene contributes to Williams syndrome, aortic stenosis and skin laxity [Tassabehji M., Metcalfe K., Hurst J., Ashcroft GS, Kielty C., Wilmont C., Donnai D., Read AP And Jones C.J. (1998) “An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibers in a patient with autosomal dominant cutis laxa” in Hum. Mol. Genet. 6: 1021-1028.

Elastic fibers have the purpose of maintaining elasticity throughout a person's life. However, there is an enzyme that degrades this elastic fiber and causes skin elasticity loss that plays an important role in skin exacerbation by sun exposure as a factor that seriously affects the aging of connective tissue [Watson R.E.B., Griffiths C.E.M., Shuttleworth C.A. And Kielty CM (1999) "Fibrillin-rich microfibrils are reduced in photoaged skin. Fibrillin-rich microfibrils are reduced in photoaged skin. Distribution at the dermal-epidermal junction J. Invest. Fermatol. 112: 782-787.

Elastase is an enzyme belonging to the serine protease system having a hydrocarbon attached to its surface. The enzyme's biological function is to break down elastin and allow neutrophil migration through connective tissue, destroying it when infected with pathogenic microorganisms. In humans, there are two genes encoding elastase, the pancreatic elastase gene and the neutrophil elastase gene, which are produced by cells such as neutrophils, macrophages, fibroblasts and pancreatic cells. Produced and secreted. Another form of elastase is found in microbes and some snake venom. The role of elastase is associated with degrading skin elasticity, health and quality. For some diseases, elastase activity is described as a direct or indirect cause of skin syndromes such as stretch marks and wrinkles due to aging and photoaging, bullous pemphigoid, dermatitis and psoriasis. Elastase activity is also associated with wound healing disorders such as keloids and hypertrophic scars and skin changes resulting from lack of elasticity, such as orange peel skin in the case of cellulite. Because elastic fibers are slow to rebuild, they do not form at the site of the wound until after some time. That is, it does not exist in recent scars, and its arrangement is abnormal in mature scars.

Collagen is the major fibrous protein family of extracellular matrix and accounts for 25% of total protein in mammals. Collagen is classified into more than 20 systems, all of which have individual properties that satisfy specific tissue-specific functions.

The main feature of collagen is the helical structure formed by the binding of three polypeptide chains rich in glycine and proline. Changes in this amino acid composition lead to abnormalities and loss of mechanical properties [Culav E.M., Clark C.H. And Merrilees M.J. (1999) "Connective tissues: matrix composition and its relevance to physical therapy" Phys. Ther. 79: 308-319. In mature tissue, these polypeptide chains can bind to each other to form fibrils 10-300 nm in diameter and hundreds of microns in length. This fibrils can be added to the main structure as cable bunching, which can be observed through the electron microscope as collagen fibers of several micro diameters. This process is known as fibrillogenesis [Aumailley M. and Gayraud B. (1998) "Structure and Biological activity of the extracellular matrix" J. Mol. Med. 76: 253-265. Not all collagen have the ability to form fibrils; Only collagen I, II, III, V and XI, known as fibrillar collagen, have the ability to form fibrils.

Adult dermis is basically formed by I, II, III, V and XI fibrila collagen. Type I fibrila collagen accounts for 80-90% of the total collagen in the dermis. In general, Type I fibrila collagen has a relatively large diameter, which is related to its ability to withstand higher mechanical loads. Type III collagen is involved in tissue extensibility, and as aging progresses, it is replaced by a type I collagen molecule, which is partly responsible for the phenomenon that mature skin is less stretchable than young skin. Collagen V, together with type I and III collagen, regulates the diameter of fibrils ("The Biology of the Skin", Freinkel RK and Woodley DT, eds. The Parthenon Publishing Group, 2001 ; Culav EM, Clark CH and Merrilees MJ (1999) "Connective tissues: matrix composition and its relevance to physical therapy" Phys. Ther. 79: 308-319.

Collagen fibers undergo a continuous regeneration process. However, this regeneration decreases as aging progresses, which shrinks the dermis. In addition, even though the collagen network has a high resistance due to collagen fiber organization, collagen fibers are sensitive to certain enzymes known as matrix metalloprotease (MMP). MMPs have a zinc atom coordinated with three cysteine residues and one methionine residue at the active center, and proteolytic enzymes capable of co-degrading the macromolecular components (collagen, elastin, etc.) of the extracellular matrix and base plate to neutral pH ( Endoproteinase).

The coagulation of the dermis is mainly due to the overlapping of the filled collagen fibers against each other in all directions. Collagen fibers aid in the elasticity and tension of the skin and / or mucous membranes. However, the atrophy of the dermis is not only due to natural aging, but also pathological causes such as, for example, corticosteroid oversecretion, certain diseases (Marpine syndrome, Ehlers-Danlos Syndrome) or vitamin deficiency (scurvy). to be. It is also recognized that external factors, such as ultraviolet radiation, tobacco, or certain treatments such as retinoic acid and derivatives, glucorotinoids or vitamin D and derivatives, also affect the skin, mucous membranes and / or scalp and the amount of collagen. something to do. Due to the breakdown of collagen fibers, drooping and wrinkled skin in areas of skin exposed to sunlight, such as the face, ears, neck, scalp, arms and hands, which people always try to remove because they prefer skin that looks smooth and taut. Brings about.

Skin damage associated with chronic exposure (repeated irradiation) or strong exposure (strong irradiation) to UVA and / or UVB rays was studied. In particular, UVB rays with more intense wavelengths (290-300 nm; 5% of total UV light) affect epidermal cells (keratinocytes), which in particular act on DNA, and UVA rays (320-400 nm; total UV light). 95%) has a stronger permeability and also indirectly acts on dermal cells such as fibroblasts and generates free radicals.

In addition, prolonged exposure to UV rays, particularly UVA and / or UVB rays, promotes MMP expression that disrupts collagen [Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J., Kang S., and Voorhees JJ ( 1996) "Molecular basis of sun-induced premature skin ageing and retinoid antagonism" Nature 379: 335-339 ; Fisher GJ, Wang ZQ, Datta SC, Varani J., Kang S., and Voorhees JJ (1997) "Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light" New Eng. J. Med. 337: 1419-1429 ; Fisher GJ, Choi HC, Bata-Csorgo Z., Shao Y., Datta SC, Wang ZQ, Kang S., and Voorhees JJ (2001) "Ultraviolet irradiation is a matrix metalloproteinase-8 protein in human skin in vivo. (Ultraviolet irradiation increases matrix metalloproteinase-8 protein in human skin in vivo) ", in particular, it promotes the expression of type 1 substrate metalloelastatase (MMP-1). This material is one of the components of skin aging or photoaging induced by light [Rittie L. and Fisher GL (2002) “UV Light-induced signal cascades and skin aging” "Ageing Res. Rev. 1: 705-720. In addition, it is known that as aging progresses, MMP-1, MMP-2 and MMP-9 activities are increased, which is attributed to natural skin aging with decreased cell growth [EP 1005333 B1]. Similarly, smoker's skin also has fast aging characteristics overexpressing MMPs [Lahmann C., Bergemann J., Harrison G., and Young AR (2001) "Substrate Metalloproteinase-1 and Skin of Smokers""Matrix metalloproteinase-1 and skin aging in smokers" Lancet 357: 935-936.

Elastic fibers have a decrease in overall elasticity by increasing crosslinking with time, and at the same time, the dermal density decreases due to gradual fragmentation of elastin. Such changes include loss of skin elasticity and the production of signs of aging. In addition, damage to the extracellular matrix induced by UV light causes wrinkles, loss of skin recovery, and actinic elastosis. Elastic fibrosis is visible to the naked eye as yellow bumps on the exposed skin. Histologically, elastic fibrosis refers to the accumulation of basophilic amorphous substances in the papillary dermis consisting of elastin, microfibril protein, fibronectin and type I and III collagen.

The most obvious sign of aging is the formation of wrinkles due to loss of skin elasticity. In molecular terms, the elastic fibers have a linear appearance that suggests elasticity in young skin. Bent or shredded fibers indicate lack of elasticity and are associated with aging [Imokawa G., Takema Y., Yorimoto Y., Tsukahara K., Kawai M. and Imayama S. (1995) "Elastic fibers in rat skin Degree of UV-induced tortuosity of elastic fibers in rat skin is age dependent. "J. Invest. Dermatol. 105: 254-258. Improvements in skin wrinkles induced by materials such as trans-retinoic acid or by CO ₂ laser include restoring linearity of elastic fibers [Tsukahara K., Kawai M., Fujimura T., Imayama S. and Imokawa G. (2001) "Carbon dioxide laser treatment promotes repair of the three-dimensional network of elastic fibers in rat skin" Br. J. Dermatol. 144: 452-458 ; Tsukahara K., Takema Y., Moriwaki S., Kitahara T., Imayama S. and Imokawa G. (1999) "All trans retinoic acid promotes the recovery of three-dimensional networks of elastic fibers in rat skin (All-trans retinoic). acid promotes repair of the three-dimensional network of elastic fibers in rat skin) "Br. J. Dermatol. 140: 1048-1053]. The loss of linearity of the elastic fibers is due to the secretion of elastase by the surrounding fibroblasts, which may be accompanied by the absence of endogenous elastase inhibitors. In addition, ultraviolet B (UV B) irradiation results in loss of linearity and consequently loss of flexibility by stopping fibroblasts from maintaining tension on the elastic fibres. Specific inhibition of cutaneous elastase inhibits wrinkles, delays loss of skin elasticity and slows down the breakdown of the three-dimensional structure of elastic fibers [Tsukahara K., Takema Y., Moriwaki S., Tsuji N., Suzuki y., Fujimura T. and Imokawa G. (2001) "Selective inhibition of skin fibroblast elastase elicits a concentration-dependent prevention of skin fibroblast elastase enables selective inhibition of skin fibroblast elastase elicits by concentration-dependent UVB-induction. of ultraviolet B-induced wrinkle formation) "J. Invest. Dermatol. 117: 671-677. Therefore, by inhibiting elastase activity by topical application, it is possible to reduce, prevent or delay the signs of aging and photoaging such as wrinkles, spots and impression lines.

In addition, during menopause, the major changes associated with the dermis are a decrease in the amount of collagen and the thickness of the dermis. In postmenopausal women, this results in atrophy of the skin and / or mucous membranes. Thus, the woman has a feeling of "dry skin" or a pulling of the skin, an increase in the amount of surface wrinkles and fine lines are observed. The skin looks rough. In addition, the skin is less supple. Women lose 2.1% of their collagen levels each year after menopause and 30% of their first five years after menopause [Brincat M., Kabalan S., Studd JW, Moniz CF, de Trafford J. and Montgomery J. (1987) "A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman" Obstet. Gynecol. 70: 840-845.

Proteolytic enzymes play an important role in various skin, mucosal and / or scalp diseases and disorders in which the breakdown and destruction of collagen and / or elastin occurs. [Kahari VM and Saarialho-Kere U. (1997) Matrix metalloproteinase in skin "Exp. Dermatol. 6: 199-213. Among various diseases in which collagen is degraded due to the activity of protease in connective tissue cells, the inventors have found that chronic ulcers [Miyoshi H., Kanekura T., Aoki T. and Kanzaki T. (2005) "metalloproteinases. Beneficial effects of tissue inhibitor of metalloproteinases-2 (TIMP-2) on chronic dermatitis. "J. Dermatol. 32: 346-353, psoriasis [Flisiak I., Mysliwiec H. and Chodynicka B. (2005) "Plastics of Psoriasis Treatment on Plasma Concentrations of Metalloproteinase-1 and Tissue Inhibitors of Metalloproteinase-1 Effect of psoriasis treatment on plasma concentrations of metalloproteinases-1 and tissue inhibitor of metalloproteinases-1 "J. Eur. Acad. Dermatol. Venereol. 9: 418-421 ; Suomela S., Kariniemi AL, Impola U., Karvonen SL, Snellman E., Uurasmaa T., Peltonen J., Saarialho-Kere U. (2003) "Substrate metalloproteinases by keratinocytes in psoriasis- Matrix metalloproteinases-19 is expressed by keratinocytes in psoriasis. "Acta Derm. Venereol. 83: 108-114], oral abnormalities such as gingivitis and periodontitis [Reynolds JJ and Meikle MC (1997) "The functional balance of metalloproteinases and inhibitors in tissue degradation: The functional balance of metalloproteinases and inhibitors in tissue degradation: revelance to oral pathologies) "JR Coll. Surg. Edinb. 42: 154-160, skin cancer [Ntayi C., Hornebeck W. and Bernard P. (2004) "Involvement of matrix metalloproteinases (MMPs) in cutaneous melanoma progression in skin melanoma progression. ) "Pathol. Biol. (Paris) 52: 154-159 ; Kerkela E. and Saarialho-Kere U. (2003) "Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer" Exp. Dermatol. 12: 109-125, and tumor infiltration and metastasis [Sato H., Takino T., and Miyamori H. (2005) "The Role of Membrane Substrate Metalloproteinase-1 in Tumor Infiltration and Metastasis (Roles of membrane) -type matrix metalloproteinase-1 in tumor invasion and metastasis) "Cancer Sci. 96: 212-217.

Proteases also play an important role in different physiological situations in which extracellular matrix is degraded or reconstituted, such as tissue morphogenesis, tissue repair, and neovascularization, including neovascularization. Kahari VM And Saarialho-Kere U. (1997) "Matrix metalloproteinases in skin" Exp. Dermatol. 6: 199-213. In certain situations, MMPs play a decisive role in connective tissue remodeling [Abraham D., Ponticos M. and Nagase H. (2005) “Connective tissue remodeling: crosstalk between endothelin and matrix metalloproteinases ( Connective tissue remodeling: cross-talk between endothelins and matrix metalloproteinases) "Curr. Vasc. Pharmacol. 3: 369-379], for example, collagen breakdown by MMP makes the skin appear wrinkled and sagging.

Another skin and / or scalp disease or condition associated with MMP overexpression or increased MMP activity in connective tissue is acne [Papakonstantinou E., Aletas AJ, Glass E., Tsogas P., Dionyssopoulos A., Adjaye J., Fimmel S., Gouvousis P., Herwig R., Lehrach H., Zouboulis CC And Karakiulakis G. (2005) "Matrix metalloproteinases of epithelial origin in facial serum of patients with acne and their regulation by isotretinoin" J. Invest. Dermatol. 125: 673-684. Skin with acne is described to contain high levels of MMP-1.

Fibroblasts are one of the cells that secrete elastase, and elastase produced by neutrophils contributes to the development of skin diseases or even diseases. Neutrophil elastase or Human Leukocyte Elastase (HLE) is a proinflammatory agent known to be able to degrade several components of extracellular matrix such as elastin, type III and type IV collagen and proteoglycans. Neutrophil elastase activity is increased on the surface of diseased skin in patients with psoriasis, atopic dermatitis and allergic contact dermatitis, diseases characterized by leukocyte infiltration of the skin [Wiedow O., Wiese F. , Streit V., Kalm C. and Christophers E. (1992) "(Lesional elastase activity in psoriasis, contact dermatitis and atopic dermatitis)" J. Invest. Dermatol. 99: 306-309. In addition, leukocyte infiltration of the skin is increased by UV light [Woodbury R.A., Kligman L.H., Woodbury M.J. And Kligman A.M. (1994) "Rapid assay of the anti-inflammatory activity of topical corticosteroids by inhibition of UVA-induced neutrophil infiltration in hairless mouse skin. I. Rapid assay of the anti-inflammatory activity of topical corticosteroids by inhibition of a UVA-induced neutrophil infiltration in hairless mouse skin. I. The assay and its sensitivity) "Acta Derm. Venereol. 74: 15-17. In addition, elastin degradation by elastase produces elastin fragments that act as cytokines that contribute to chronic inflammatory conditions associated with aging [Antonicelli F., Bellon G., Debelle L. and Hornebeck W. (2007) "Elastin-elastase and inflamm-aging" Vurr. Top. Dev. Biol. 79: 99-155.

Psoriasis is a chronic skin inflammation of unknown cause. The development of psoriasis is associated with an inflammatory response mediated by components of the immune system. The main feature of this disease is the development of proliferative keratinous lesions accompanied by lymphocyte infiltration. This lesion extends at the edge, which is the site of high proliferative activity. Elastase has been shown to induce keratinocyte proliferation [Rogalski C., Meyer-Hoffert U., Proksch E. and Wiedow O. (2002) "Human leukocyte elastase is a keratinocyte in vitro. Induce proliferation (Human leukocyte elastase induces keratinocyte proliferation in vitro and in vivo) "J. Invest. Dermatol. 118: 49-54. These data suggest that skin compositions containing compounds that inhibit elastase enzymatic activity may be used to reduce the amount of elastase, for example, for the treatment of psoriasis, atopic dermatitis and allergic contact dermatitis. Increasingly, it means that it is a suitable way to alleviate diseased skin symptoms in which inflammation and leukocyte infiltration occur. People with dermatitis, including contact dermatitis and atopic dermatitis, are also high in some MMPs [Herouy Y., Mellios P., Bandemir E., Dichmann S., Nockwski P., Schopf E., and Norgauer J. (2001). "Inflammation in stasis dermatitis upregulates MMP-1, MMP-2 and MMP-13 expression" J. Dermatol. Sci. 25: 198-205 ; Devillers AC, van Toorenenbergen AW, Klein Heerenbrink GJ, Muldert PG, and Oranje AP (2007) "Increase the level of plasma matrix metalloproteinase-9 in patients with atopic dermatitis: an elevated level of plasma matrix metalloproteinase- 9 in patients with atopic dermatitis: a pilot study "Clin.Exp. Dermatol. 32: 311-313 ; Miyoshi H., Kanekura T., Aoki T. and Kanzaki T. (2005)" Metaloproteinase-2 ( Bendicial effects of tissue inhibitor of metalloproteinase-2 (TIMP-2) on chronic dermatitis "J. Dermatol. 32: 346-353]. Skin diseases, disorders or diseases causing inflammation, including dermatitis, atopic dermatitis, sensitive skin and eczema.

Similarly, rosacea is a skin and / or scalp disease or condition involving MMPs. Injections are characterized by neovascularization and increased inflammation. Angiogenesis refers to the formation of new blood vessels, including benign conditions such as injections and malignant symptoms such as cancer. Matrix degrading enzymes present in tissue extracellular matrix promote new blood vessel formation because they allow new blood vessels to penetrate the substrate. MMP is one of the enzymes involved in this process [Sapadin A.N., Fleischmajer R. (2006) "Tetracyclines: Nonantibiotic properties and their clinical implications" J. Am Acad. Derm. 54: 258-265.

Another inflammatory skin disease is bullous pemphigoid, which causes blistering. Neutrophils are involved in the development of dermal lesions of bullous ulcers, and their action is mediated by elastase [Liu Z., Shapiro S.D., Zhou X., Twining S.S., Senior R.M., Giudice G.J., Fairley J.A. And Diaz L.A. (2000) "A critical role for neutrophil elastase in experimental bullous pemphigoid." J. Clin. Invest. 105: 113-123], topical application of elastase inhibitors may be a potential effective treatment for alleviating these skin disease symptoms.

Inhibition of elastase also has other effects, as described in the literature. For example, US Pat. No. 7,211,278 discloses the use of elastase inhibitors as adjuvants in cosmetic compositions for the purpose of inhibiting hair growth for use in applications such as hair removal.

It is also known that MMPs are involved in periphery of hair follicle matrix degradation and are therefore associated with hair loss. In particular, cytokines and epidermal growth factors promote MMP-9 production in the low epithelial region of the hair roots, and this mechanism regulates hair follicle degeneration observed in alopecia [Jarrousse F., Boisnic S., Branchet MC, Beranger JY, Godeau G., Breton L., Bernard BA And Mahe Y.F. (2001) "Identification of clustered cell in human hair follicle responsible for MMP-9 gelastinolytic activity: consequences for the regulation of hair growth) "Int. J. Dermatol. 40: 385-392. Therefore, inhibition of overexpressed MMPs in the course of hair loss may be effective in delaying and further preventing hair loss [EP 1 076 549 B1].

MMP activity is also involved in the scar formation of collagen-containing tissues. "Scar formation" refers to the formation of abnormal histological collagen structures due to the repair process of tissues containing collagen on the skin or due to previous injuries.

The recovery process consists of three stages: (1) inflammatory phase, (2) granulation tissue generation, and (3) wound tissue remodeling phase. An essential step in the recovery process is to break down the extracellular matrix. In order for the cells to proliferate and regenerate at the site of injury, the extracellular matrix is decomposed. This decomposition is done via MMP. The stage of the recovery process is controlled by the balance between the different MMPs, with excess of MMP activity causing chronic ulcers. Likewise, diabetic ulcers are characterized by prolonged inflammation, decreased collagen synthesis, and high content of MMPs.

Scars have many causes (accidents, surgical procedures, skin diseases, burns, acne infections, and common accidents), and not all scars are the same. Various types of scars can be classified as follows:

Flat, soft scars that are created as a result of the body's natural healing process

Recessed scars: created by skin associated with deep structures such as muscles or due to fat loss in internal tissues. These scars create a recess in the skin and are primarily a result of injury.

Hypertrophic scar: Appears when the body produces excess collagen during the recovery process. These scars increase on the surface of the skin and contain irregularly composed collagen.

-Keloid scars: produced as a result of an imbalance in collagen production during recovery. These scars not only increase on the surface of the skin but also extend beyond the boundaries of the original injury and can continue to grow indefinitely.

Acne scars: Produced on skin with acne. These scars can be crushed or become keloids. People who have chickenpox may have similar scars.

Stretch scars: Occurs when the skin around a recovering injury remains taut during the healing process. At first, the scar may look normal, but it becomes thinner over a few weeks or months. These scars can occur when the injury site is near the joint and pulled during movement, and can usually occur when recovery is poor due to poor health or undernutrition.

Stretch Marks: Generated when the skin swells rapidly, eg due to rapid growth during pregnancy or puberty.

Therefore, skin scar reduction is desirable as a recovery during the process of fibrosis in pathological terms and as a relief from scars due to acne or stretch marks in cosmetic terms. Potential benefits of elastase inhibition in connection with scars have also been published. There is a breakdown of elastin at the periphery of the scar caused by acne vulgaris [Dick G.F., Ashe B.M., Rodgers E.G., Diercks R.C. And Goltz R.W. (1976) "Study of elastolytic activity of Propionibacterium acnes and Staphylococcus epidermis in acne vulgaris and in normal skin" Acta Derm . Venereol. 56: 279-282. Thus, elastase inhibitors are effective as an adjunct to topical application compositions for preventing scar formation in acne-prone skin. In addition, US Pat. No. 5,922,319 describes the application of an elastase inhibitor to prevent the formation of scars on the cornea in case of eye trauma.

It has also been reported that MMPs are overexpressed during adipocyte proliferation and differentiation [Traurig M.T., Permana P.A., Nair S., Kobes S., Bogardus C. and Baier L.J. (2006) "(Differential expression of matrix metalloproteinase 3 (MMP 3) in preadipocytes / stromal vascular cells from nonobese nondiabetic versus obese nondiabetic Pima Indians)" Diabetes 55: 3160-3165]. The collagen network of cellulite-based skin is destroyed, which is one of the causes of orange skin appearance. Therefore, supplementing the skin with a compound that can promote collagen synthesis will help reduce collagen breakdown and provide effective anticellulite treatment. In addition, inhibiting elastase also reduces collagen degradation effects, for example, to prevent spot formation resulting from aging and to improve skin irregularities such as orange peel skin, which is characteristic of cellulite.

MMP activity also contributes to the dissolution of extracellular matrix around lymphatic vessels and blood vessels. Substrate division around blood vessels leads to passive vasodilation, or couperosis, which leads to capillary thorn or capillary distension. In addition, such microcapillary passive dilatation can cause local vascular rupture that can progress to sagging flesh under the eye or dark circles around the eye. In addition, MMPs can affect the mechanical properties of the vein wall, weakening the vein and consequently causing varicose veins.

Apart from the association of MMPs with tissue matrix degradation, MMPs are also associated with arthritis (rheumatic arthritis, osteoarthritis, etc.), osteopathy (such as osteoporosis), ectopic angiogenesis, multiple sclerosis, tumor metastasis and tissue ulcers ( Corneal, stomach, epidermis, etc.) and is involved in different diseases that simultaneously cause abnormal metabolism of connective tissue or basement membrane matrix [EP 0 927 161 B1]. Therefore, MMP inhibitors may be effective in treating and preventing such diseases caused by abnormal metabolism of tissue substrates.

It is thus possible to recognize the importance of the presence of collagen and elastin fibers in the skin, mucous membranes and / or scalp and of maintaining or even reinforcing their presence. Therefore, it is important to obtain a commercial product that has the effect of maintaining the amount and integrity of collagen and / or elastin in the skin, maintaining a smooth and tight skin appearance, and reducing, delaying and / or preventing the signs of aging and / or photoaging. Do. Maintaining high amounts of elastin and / or collagen in the skin or increasing elastin and / or collagen content in the skin can be accomplished by a variety of other methods. On the other hand, a substance that inhibits matrix protease can be used. However, on the other hand, substances that suitably increase collagen and / or elastin synthesis may be used by the synthesis of new pathways against the adverse effects of collagen and / or elastin degradation induced by proteases. The decrease in protein synthesis of new pathways that accompanies with age may be at least partially compensated for by using active ingredients that increase collagen and / or elastin synthesis.

In the context of the present invention, the terms "aging" and "aging skin" refer not only to changes in the appearance of the skin visible to the naked eye, but also to wrinkles, fine lines, roughness, impression lines, scratch marks, splitting, Deep wrinkles, sagging, skin off (ball off, etc.), wrinkles under the eyes, double chin, increased pore size, loss of elasticity, loss of recovery, loss of skin hardness, elastic fibrosis, abnormal differentiation, hyperkeratinization, keratosis, skin color changes ( For example, spots, reddening of the skin or sagging under the eyes, generation of hyperpigmentation sites (eg, senile spots, macula, or freckles), loss of smoothness, orange-peel skin, loss of collagen structure, and stratum corneum, dermis, vascular bundle (eg spider) Double vein or capillary telangiectasia) or other histological change of tissue adjacent to the skin. Skin aging is a process that consists of two main factors: the chronological factor over time and the light-induced factor (known as photoaging) due to the exposure to ultraviolet (UV) radiation. In addition, some environmental factors such as exposure to tobacco smoke, exposure to pollution, and climatic conditions such as cold and / or wind also contribute to skin aging.

Various plant extracts with elastase inhibitory activity [eg, JP 11-246386, JP 2000-072649, JP 11-279041, US 6,395,261, US 6,238,674], and synthetic chemical compounds having such activity [US 4,643,991, US 5,008,245, US 5,162,307, US 5,189,178 are disclosed. In particular, US Pat. No. 4,665,053 discloses synthetic lipopeptides rich in alanine and proline, particularly lipopeptides containing L-Ala-L-Ala dipeptides as elastase inhibitors.

The individual substances often mentioned in connection with the increase in collagen synthesis and thus described in the background of the invention are for example ascorbic acid and its derivatives (especially ascorbyl palmitate, magnesium ascorbyl phosphate, sodium Ascorbyl phosphate and ascorbyl alpha- and beta-glucosides), retinol and derivatives thereof (e.g. retinoic acid, retinal, retinol, retinyl acetate or retinyl palmitate), or e.g. aloe and centella It is an active ingredient such as a plant extract, such as an extract of Centella species. Active ingredients that are more frequently used to promote collagen synthesis also include peptide materials and derivatives thereof, such as carnitine, carnosine, creatine, matrikin peptides (e.g., Lysyl-threonyl-threonyl-lysyl-serine). And other peptide constructs such as palytoylated pentapeptides (eg Matrixyl® from Sederma / Croda) or oligopeptides under the trade name Vincipeptide (Vincience, France). In addition, extracts of Asian acid, madecassic acid, madecassoside, madecassoside, asiaticoside, centella asiatica, niacinamide, astaxanthin, yeast and Glycans from soybeans, soy extracts and soy isoflavones such as genistein and daidzein, rutin, chrysin, maline, betel nut alkaloids, paulscoline, betulinic acid, Compounds such as Plantago species extract, TGF-beta, ginkgo extract, glutamine and glycolic acid are also used as collagen synthesis promoters.

The present invention describes synthetic peptides containing non-coding amino acids that are effective at inhibiting elastase and / or promoting collagen synthesis in the skin, mucosa and / or scalp. There is no prior art for peptides containing non-coding amino acids in the sequence that provide elastase inhibitory activity in the skin, mucosa and / or scalp and / or promote collagen synthesis. The use of non-coding amino acids can increase the half-life of peptides containing these amino acids by making the protease difficult to recognize. Increasing the half-life of such peptides increases the efficiency in inhibiting elastase and / or promoting collagen synthesis.

Thus, despite the presence of a number of compounds and / or extracts that have the potential to promote endogenous synthesis of collagen or elastin in the skin, mucous membranes and / or scalp, or have activity against enzymes that degrade collagen or elastin There is still a need to find new and efficient elastase inhibitors and / or collagen synthesis promoters than are known in the art.

The present invention provides a solution to the above problems. Surprisingly, the inventors have found that certain synthetic peptides containing non-coding amino acids have very high efficiencies in inhibiting elastase and / or promoting collagen synthesis in the skin, mucous membranes and / or scalp, and thus collagen synthesis. It has been found to be effective in treating, preventing and / or managing diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp that provide facilitating benefits and / or result from elastase activity.

Justice

To help the understanding of the present invention, some terms and expressions used in the specification of the present invention are described.

As used herein, the abbreviations used for amino acids are Eur. J. Biochem. (1984) 138: 9-37 and J. Biol. Chem. (1989) in accordance with the provisions of the Commission on Biochemical Nomenclature of IUPAC-IUB as set forth in 264: 633-673.

Thus, for example, Gly represents NH ₂ -CH ₂ -COOH, Gly- represents NH ₂ -CH ₂ -CO-, -Gly represents -NH-CH ₂ -COOH, and -Gly- is- NH-CH ₂ -CO- is shown. Therefore, hyphens representing peptide bonds remove OH from the 1-carboxyl group of amino acids (denoted in the conventional non-ionized form herein) when located to the right of the sign, and from 2-amino groups of amino acids to the left of the sign. H is removed and two variants can be applied simultaneously to the same sign (see Table 1).

Amino acid structure and three letter code designation sign Residue sign Residue sign Residue -Gly-

-Ala-

-Val-

-Arg-

-Cit-

-Nle-

-Trp-

-Tyr-

-Phg-

The abbreviation "Ac-" is used herein to denote an acetyl group (CH ₃ -CO-), and the abbreviation "Palm-" to denote a palmitoyl group (CH _3- (CH ₂ ) ₁₄ -CO-). Used for.

The term "acyclic aliphatic group" is used herein to mean, but not limited to, including linear or branched alkyl, alkenyl and alkynyl groups.

The term "alkyl group" is 1 to 24, preferably 1 to 16, more preferably 1 to 14, still more preferably 1 to 12, particularly preferably 1, 2 , Linear or branched saturators containing 3, 4, 5 or 6 carbon atoms, bound to the rest of the molecule by a single bond, e.g. methyl, ethyl, isopropyl, isobutyl, tert Butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl, and the like.

The term "alkenyl group" means 2 to 24, preferably 2 to 16, more than one, having one or more carbon-carbon double bonds, preferably one, two or three carbon-carbon double bonds. Conjugated or unconjugated linear, preferably containing 2 to 14, more preferably 2 to 12, particularly preferably 2, 3, 4, 5 or 6 carbon atoms Or a branched group, which is bonded to the rest of the molecule by a single bond, and is used in the sense including, but not limited to, vinyl, oleyl, linoleyl groups, and the like.

The term "alkynyl group" refers to 2 to 24, preferably 2 to 16, more than one, having at least one carbon-carbon triple bond, preferably one, two or three carbon-carbon triple bonds. Conjugated or unconjugated linear, preferably containing 2 to 14, more preferably 2 to 12, particularly preferably 2, 3, 4, 5 or 6 carbon atoms Or as a branched group, bound to the rest of the molecule by a single bond, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 Used in the sense including, but not limited to, a pentynyl group such as a pentynyl group.

The term "alicyclyl group" is used herein to mean, but is not limited to, including, for example, cycloalkyl, cycloalkenyl and cycloalkynyl groups.

The term "cycloalkyl" is 3 to 24, preferably 3 to 16, more preferably 3 to 14, even more preferably 3 to 12, particularly preferably 3, 4 Saturated mono- or polycyclic aliphatic groups containing dog, five or six carbon atoms, which are bonded to the rest of the molecule by a single bond, for example cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, methyl cyclo It is used in the sense including, but not limited to, hexyl, dimethyl cyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrofennalene group, and the like.

The term "cycloalkenyl" refers to 5 to 24, preferably 5 to 16, having one or more carbon-carbon double bonds, preferably having one, two or three carbon-carbon double bonds, Conjugated or non-conjugated non-aromatic mono- or polycyclic aliphatic groups containing more preferably 5 to 14, more preferably 5 to 12, particularly preferably 5 or 6 carbon atoms As a single bond, it is bonded to the rest of the molecule, and is used in the sense including, but not limited to, a cyclopent-1-en-1-yl group and the like.

The term "cycloalkynyl" means from 5 to 24, preferably from 5 to 16, with one or more carbon-carbon triple bonds, preferably with one, two or three carbon-carbon triple bonds, Conjugated or non-conjugated non-aromatic mono- or polycyclic aliphatic groups containing more preferably 5 to 14, more preferably 5 to 12, particularly preferably 5 or 6 carbon atoms As a single bond, it binds to the rest of the molecule, and is used in the sense including, but not limited to, a cyclohex-1-yn-1-yl group.

 The term "aryl group" means from 6 to 30, preferably from 6 to 18, more preferably from 6 to 10, even more preferably having 1, 2, 3 or 4 aromatic rings Preferably an aliphatic group containing 6 or 10 carbon atoms, bonded or fused by carbon-carbon, for example, a phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranilic group, or an aralkyl group Used in the sense including, but not limited to.

The term "aralkyl group" means that the carbon of the alkyl group is substituted with an aromatic group containing 7 to 24 carbon atoms, for example-(CH ₂ ) _1-6 -phenyl,-(CH ₂ ) _1-6- ( 1-naphthyl),-(CH ₂ ) _1-6- (2-naphthyl),-(CH ₂ ) _1-6 -CH (phenyl) ₂ and the like, but is not limited thereto.

The term "heterocyclyl group" refers to a hydrocarbon ring having 3 to 10 members, in which at least one atom, preferably one, two or three atoms, of the ring are not carbon, e.g. nitrogen, oxygen Or sulfur or saturated or unsaturated group. For the purposes of the present invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may comprise a fused ring system, optionally wherein nitrogen, carbon or sulfur atoms may be oxidized in the heterocyclyl group. Optionally, the nitrogen atom may be quaternized, and the heterocyclyl group may be a partial or fully saturated group or an aromatic group. In terms of preference, the term heterocyclyl means a five or six-membered ring.

The term "heteroarylalkyl group" means that the carbon of the alkyl group is substituted with a substituted or unsubstituted aromatic heterocyclyl group, wherein the alkyl group contains 1 to 6 carbon atoms and the aromatic heterocyclyl group is 1 to 24 carbon atoms and 1 Containing from 3 to 3 non-carbon atoms, for _example- (CH ₂ ) _1-6 -imidazolyl,-(CH ₂ ) _1-6 -triazolyl,-(CH ₂ ) _1-6 -thier Used in the sense including, but not limited to, a-(CH ₂ ) _1-6 -furyl,-(CH ₂ ) _1-6 -pyrrolidinyl group, and the like.

When used in the technical scope, there may be substitutions for the groups defined above. Thus, substitutions may be present for any group in the present invention. References to substituents in the groups of the present invention refer to one or more substituents in which a particular group is at one or more effective positions, preferably at 1, 2 or 3 positions, more preferably at 1 or 2 positions, particularly preferably at 1 position It can be substituted by. Such substituents include, for example, C ₁ -C ₄ alkyl; Hydroxyl; C ₁ -C ₄ alkoxy; Amino; C ₁ -C ₄ aminoalkyl; C ₁ -C ₄ carbonyloxy; C ₁ -C ₄ oxycarbonyl; Halogen such as fluorine, chlorine and iodine; Cyano; Nitro; Azido; C ₁ -C ₄ alkylsulfonyl; Thiols; C ₁ -C ₄ alkylthio; Aryloxyl, such as phenyloxyl; -NR _b (C = R _b ) NR _b R _c (wherein R _b and R _c are H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₈ aryl, C ₇ -C ₁₇ aralkyl, independently selected from the group consisting of 3 to 10 ringmembers heterocyclyl or amino group protecting groups), and the like. It doesn't happen.

The compound of the present invention

Compound of the present invention is a peptide defined by the following formula (1),

[Formula 1]

R ₁ -W _p -X _n -AA ₁ -AA ₂ -AA ₃ -AA ₄ -Y _m -R ₂

As stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, at least one of the amino acids AA ₁ , AA ₂ and AA ₄ is a non-coding amino acid,

AA ₁ is selected from the group consisting of -Arg-, -Phg- and -Nle- or is one bond,

AA ₂ is selected from the group consisting of -Ala-, -Phg-, -Cit- and -Nle-,

AA ₃ is selected from the group consisting of -Trp-, -Val- and -Tyr-,

AA ₄ is selected from the group consisting of -Phg- and -Gly-;

W, X and Y are independently selected from the group consisting of coding or non-coding amino acids,

p, n and m are 0 to 1,

R ₁ is H, substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted Or unsubstituted aralkyl and R ₅ -CO-,

R ₂ is selected from the group consisting of -NR ₃ R ₄ , -OR ₃ and -SR ₃ ,

Wherein R ₃ and R ₄ are H, substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Independently selected from the group consisting of substituted aryl and substituted or unsubstituted aralkyl,

R ₅ is H, substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or Selected from the group consisting of unsubstituted heteroarylalkyl,

If AA ₁ is one bond, AA ₂ is -Phg- and AA ₃ is -Trp-.

The R ₁ and R ₂ groups are each associated with the amino-terminus (N-terminus) and carboxy-terminus (C-terminus) of the peptide sequence.

According to a preferred embodiment of the invention, R ₁ is selected from the group consisting of H and R ₅ -CO-, wherein R ₅ is substituted or unsubstituted C ₁ -C ₂₄ alkyl, substituted or unsubstituted C _2- C ₂₄ alkenyl, substituted or unsubstituted C ₂ -C ₂₄ alkynyl, substituted or unsubstituted C ₃ -C ₂₄ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkynyl, substituted or unsubstituted C ₆ -C ₃₀ aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, substituted or unsubstituted heterocycle with 3 to 10 ring members Reel, and substituted or unsubstituted heteroarylalkyl containing an alkyl chain having 2 to 24 carbon atoms and 1 to 3 non-carbon atoms and having 1 to 6 carbon atoms. More preferably, R ₁ is H, acetyl, tert -butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, Oleyl and linoleyl groups. More preferably, R ₁ is selected from H, acetyl, lauroyl, palmitoyl, or myristoyl groups. In a particularly preferred embodiment, the R ₁ group is an acetyl group.

According to another preferred embodiment of the invention, R ₂ is -NR ₃ R ₄ , -OR ₃ or -SR ₃ , wherein R ₃ and R ₄ are H, substituted or unsubstituted C ₁ -C ₂₄ alkyl, Substituted or unsubstituted C ₂ -C ₂₄ alkenyl, substituted or unsubstituted C ₂ -C ₂₄ alkynyl, substituted or unsubstituted C ₃ -C ₂₄ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cyclo Alkenyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkynyl, substituted or unsubstituted C ₆ -C ₃₀ aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, 3 to 10 ring members Substituted or unsubstituted heterocyclyl having a substituted or unsubstituted heteroarylalkyl having an alkyl chain having 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and having 1 to 6 carbon atoms Independently from the group consisting of: Optionally, R ₃ and R ₄ may form a ring with nitrogen atoms by bonding by a carbon-carbon bond as a saturated or unsaturated group. More preferably, R ₂ is —NR ₃ R ₄ or —OR ₃ , wherein R ₃ and R ₄ are H, substituted or unsubstituted C ₁ -C ₂₄ alkyl, substituted or unsubstituted C ₂ -C ₂₄ eggs Kenyl, substituted or unsubstituted C ₂ -C ₂₄ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted with 3 to 10 ring members Or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl having an alkyl chain of 3 to 10 ring members and 1 to 6 carbon atoms. More preferably, R ₃ and R ₄ are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. Especially preferably, R ₃ is H and R ₄ is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. According to a more preferred embodiment of the invention, R ₂ is selected from —OH or —NH ₂ .

In another embodiment of the invention, AA ₂ is -Phg- and AA ₄ is -Phg-.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl and palmitoyl groups, AA ₁ is -L-Arg-, AA ₂ is -L-Phg -Or -D-Phg-, AA ₃ is -L-Tyr-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , the R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Nle-, AA ₂ is -L-Phg -Or -D-Phg-, AA ₃ is -L-Tyr-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , the R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg Or D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Nle-, AA ₂ is -L-Phg Or D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg -Or -D-Phg-, AA ₃ is -L-Val-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , the R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg -Or -D-Phg-, AA ₃ is -L-Val-, AA ₄ is -Gly- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , the R ₃ and R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, and AA ₁ is -L-Phg- or -D-Phg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg- and R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl, or palmitoyl group, AA ₁ is one bond, AA ₂ is -L-Phg Or D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , R ₃ And R ₄ is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Preferably, R ₂ is -OH or -NH ₂ . More preferably, R ₁ is acetyl and R ₂ is -OH. More preferably, p, n and m are zero.

In another embodiment of the invention, R ₁ is H, acetyl, lauroyl, myristoyl, and Selected from the group consisting of palmitoyl groups, preferably R ₁ is selected from the group consisting of H, acetyl and palmitoyl, and preferably R ₂ is selected from the group consisting of -OH and -NH ₂ .

Preferably the compound of formula 1 is selected from the group consisting of the following compounds, their stereoisomers, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts.

The peptides of the present invention may exist as stereoisomers or stereoisomeric mixtures, for example, the amino acids forming the stereoisomers may have an L-configuration, or a D-stereoconfiguration, independently of one another. Can be racemic. Therefore, it is possible to obtain racemic mixtures or diastereomeric mixtures as well as isomeric mixtures, depending on the number of asymmetric carbons and what isomers or isomer mixtures are present. Preferred constructs of the peptides of the present invention are pure isomers, ie enantiomers or diastereomers.

For example, where AA ₁ is -Phg-, it should be understood that AA ₁ is selected from -L-Phg-, -D-Phg- or mixtures thereof (racemate or non-racemate). Likewise, when AA ₂ is -Arg-, it should be understood that AA ₂ is selected from -L-Phg-, -D-Phg- or mixtures thereof (racemic or non-racemic). The manufacturing processes described herein enable those skilled in the art to obtain the stereoisomers of each of the peptides of the invention by selecting amino acids having suitable conformations.

In the context of the present invention, "non-coding amino acid" means a natural or non-natural amino acid not encoded by the genetic code, for example, citrulline, ornithine, sarcosine, desmosin, norvaline, 4-aminobutyl acid, 2-aminobutyl acid, 2-aminoisobutyl acid, 6-aminohexanoic acid, 1-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chloro Phenylalanine, 2,3-Dianopropionic acid, 2,4-diaminobutyl acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxypyrroline, allo-isorocin, allo-threonine , Isonifecotic acid, isoserine, phenylglycine, statin, β-alanine, norleucine, N-methyl amino acid, β-amino acid or γ-amino acid, and derivatives thereof, and the like, but are not limited thereto. A list of non-natural amino acids is given in the literature "Unusual amino acids in peptide synthesis" [DCRobert and F. Velaccio, in The Peptides, Vol 5 (1983), Chapter VI, Gross E. and Meienhofer J. , Academic Press, New York, USA], or NeoMPS, Badhem, Novabiochem, Sigma-Aldrich, Peptides International, Advanced Chem Tech. It can be found in commercial catalogs of specialized companies such as Chem-Implex, Maybridge Chemical Technology Chirotech, Peninsula Laboratories or RSP Amino Acid Analogues.

In the context of the present invention, when p, n and m are not zero, the nature of W, X and Y does not interfere with the activity of the peptides of the invention, but rather contributes to the inhibition of elastase and / or collagen synthesis It does not promote or have no effect.

Also within the scope of the present invention are cosmetic or pharmaceutically acceptable salts of the peptides provided by the present invention. The term "cosmetic or pharmaceutically acceptable salts" means salts that are permitted for use in animals, especially humans, and are salts used to form base addition salts, for example lithium, sodium, potassium, Inorganic salts such as, but not limited to, calcium, magnesium, manganese, copper, zinc, or aluminum, or ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histinine, or piperazine Organic salts such as, but not limited to; Or as salts used to form acid addition salts, for example acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate , Organic salts such as, but not limited to, trifluoroacetate, oleate, pamoate or gluconate, or inorganic salts such as, but not limited to, chlorides, sulfates, borates, or carbonates. . The nature of the salt is not critical but should be a cosmetic or pharmaceutically acceptable salt. Cosmetic or pharmaceutically acceptable salts of the peptides of the invention can be obtained by conventional methods well known in the art [S.M. Berge, L.D. Bighley and Monkhouse D.C. (1977) “Pharmaceutical Salts” J. Pharm. Sci. 66: 1-19.

Another aspect of the invention is a peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceuticals as described above for use in the treatment and / or care of skin, mucous membranes and / or scalp. To an acceptable salt.

In one aspect, the invention provides a compound of Formula 1 as described above for use in treating, preventing and / or managing diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp resulting from elastase activity. Peptides, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts.

In one aspect, the present invention provides a formula as described above for use in treating, preventing and / or managing diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp by providing an advantage in promoting collagen synthesis. Peptide 1, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a peptide of formula (1), stereoisomers thereof, as described above, for use in inhibiting elastase, preferably in inhibiting elastase in the skin, mucous membranes and / or scalp. Mixtures and / or cosmetically or pharmaceutically acceptable salts.

In another embodiment, the present invention provides a peptide of formula 1, stereoisomers thereof, mixtures thereof, as described above, for use in promoting collagen synthesis, preferably in promoting collagen synthesis in the skin, mucous membranes and / or scalp. And / or cosmetically or pharmaceutically acceptable salts.

In another embodiment, the present invention provides a peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceutically acceptable as described above, which increases the elasticity of the skin, mucous membranes and / or scalp. It relates to salts.

In another embodiment, the present invention provides a peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceutically acceptable as described above, which increases the elasticity of the skin, mucous membranes and / or scalp. It relates to possible salts.

In another aspect, the present invention relates to a peptide of formula (1), stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts as described above for reducing or eliminating wrinkles on the face. .

In another aspect, the invention provides a peptide of formula 1 as described above for use in treating and / or managing the skin and / or scalp by reducing, delaying and / or preventing signs of aging and / or photoaging, Stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts thereof.

In another embodiment, the invention provides wrinkles, impression wrinkles, stretch marks, skin aging, skin photoaging, wound healing disorders, ulcers, diabetic ulcers, keloids, thickening scars, acne, cellulite, orange skin, elastic tissue atrophy , Elastic fibrosis, keratosis, inflammation, dermatitis, atopic dermatitis, allergic contact dermatitis, sensitive skin, eczema, bullous swelling, gingivitis, periodontitis, skin cancer, tumor penetration, tumor metastasis, capillary dilator, cooperosis, varicose veins , Peptides of formula 1 as described above for use in treating and / or managing dark circles around the eyes, sagging sub-eyes, hair loss and hair damage, injections and / or psoriasis skin, mucous membranes and / or scalp, Stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts thereof.

In another aspect, the present invention relates to a peptide of formula (1), stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts as described above for use in hair treatment or hair hygiene. will be.

In another aspect, the present invention provides a peptide of formula 1, stereoisomers thereof, mixtures thereof, and / or the like for use in the treatment and / or care of the face and / or body or for facial and / or body hygiene. Or to cosmetic or pharmaceutically acceptable salts.

In another embodiment, the treatment, prevention and / or management of the present invention is carried out by topical or transdermal administration, preferably topical and transdermal administration is by iontophoresis, ultrasonography, electroporation, Mechanical pressure, osmotic pressure gradient, occlusive treatment, microinjection, syringeless injection by pressure or microelectric patch, or a combination thereof.

In another embodiment, the treatment, prevention and / or management of the present invention is carried out by oral administration.

Manufacturing process

Preparation of the peptides, stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts thereof of the present invention are conventional methods known in the art, for example solid phase peptide preparation methods [Stewart JM and Young JD (1984). ) "Solid Peptide Synthesis, 2nd edition" Pierce Chemical Company, Rockford, Illinois ; Bodanzsky M. and Bodanzsky A (1984) "The practice of Peptide Synthesis" Springer Verlag, New york ; Lloyd Williams P., Albericio F. and Giralt E. (1997) "Chemical Approached to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA, Solution Preparation, Solid Phase And combinations of methods for preparing solutions, or methods for preparing enzymes [Kullmann W. (1980) "Proteases as catalysts for enzymic synthesis of opioid peptides". J. Biol. Chem. 255: 8234-8238. Peptides can also be obtained by bacterial strains, genetically or otherwise, to produce the desired sequence, or by hydrolysis regulation of animal or vegetable, preferably plant proteins, to produce peptide fragments having at least the desired sequence. have.

For example, the method for preparing the peptide of formula 1 of the present invention includes the following steps.

Binding an amino acid having a C-terminus that is free of N-terminus and protected or bound to a solid support, wherein the amino acid has no C-terminus and a protected N-terminus;

Removing the protecting group at the N-terminus;

Repeating the sequence of binding and protecting group removal at the N-terminus to obtain the desired peptide sequence;

Removing the protecting group at the C-terminus or cleaving from the solid support

Preferably, the C-terminus is bonded to the solid support, the process is carried out in the solid phase, the amino acid having a C-terminus which is free of N-terminus and bonded to the polymer support, which is free of C-terminus and protected N-terminus. Binding an amino acid with; Removing the protecting group at the N-terminus; And repeating the above sequence as many times as necessary to obtain tetrapeptide, and then cleaving the prepared peptide from the original polymer support.

The functional groups of the side chains of the amino acids remain adequately protected with temporary or permanent protecting groups during the preparation process and can be deprotected simultaneously or orthogonally in the process of cleaving the prepared peptides from the polymer support.

Alternatively, it may be carried out by a convergent strategy in which the dipeptide or tripeptide is bound to the polymer support or to the dipeptides or amino acids already bound to the polymer support. Converged preparation methods are well known to those skilled in the art and described in Lloyd-Williams P., Albericio F. and Giralt E. (1997) "Convergent solid phase peptide synthesis" (1993) Tetrahedron 49: 11065- 11133, which is incorporated herein by reference.

The manufacturing process may further comprise deprotecting the N-terminus and C-terminus using standard conditions and methods known in the art and / or cleaving the peptide from the polymeric support in a general order. After this step, the functional group of the distal end can be modified. Optional modification of the N-terminus and C-terminus can be carried out with the peptide of formula 1 attached to the polymer support, or after the peptide has been cleaved from the polymer support.

Alternatively, R ₁ can be introduced by reacting the N-terminus of the peptide of the invention with compound R ₁ -Z. Here, R ₁ has the meaning described above, Z is a leaving group (leaving group), for example, but is not limited to a tosyl group, a mesyl group and a halogen group. R ₁ may also be introduced by nucleophilic substitution in the presence of a base in a suitable solvent. Here, fragments with functional groups that do not participate in NC bond formation are suitably protected with temporary or permanent protecting groups.

Optionally and / or additionally, the R ₂ groups are suitable solvents and bases (eg, N, N-diisopropylethylamine (DIEA) or triethylamine), or additives (eg, 1-hydroxybenzo Triazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt)) and in the presence of a dehydrating agent (for example carbodiimide, uronium salt, phosphonium salt or amidinium salt), or an acyl halide, for example By prior generation of thionyl chloride, the compound HR ₂ (wherein R ₂ is —OR ₃ , —NR ₃ R ₄ or —SR ₃ ) is introduced by reacting with a complementary fragment corresponding to the peptide of formula 1 It is possible to obtain a peptide of formula 1 according to the present invention. Here, fragments with functional groups that do not participate in NC bond formation are suitably protected with temporary or permanent protecting groups. Alternatively, other R ₂ groups may be introduced by a bond which occurs concurrently with the process of cleaving the peptide from the polymer support.

Those skilled in the art will readily understand that the deprotection / cleavage of C- and N-terminus and subsequent derivatization steps can be performed in a general order according to procedures known in the art [Smith, M.B. And March, J. (1999) "March's Advanced Organic Chemistry: Reations, Mechanisms and Structure", 5th Edition, John Wiley & Sons, 2001].

As used herein, the term "protecting group" refers to a group that blocks unwanted reactions of organic functional groups and can be removed under controlled conditions. Protecting groups, their state reactivity, inactivating conditions, and the like are known to those skilled in the art.

Representative examples of protecting groups for amino groups include amides such as amide acetate, amide benzoate, amide pivalate; Carbamates such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ), tert -butyloxycarbonyl (Boc), 2,2,2 Trichloroethoxycarbonyl (Troc), 2- (trimethylsilyl) ethyloxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), trityl (Trt) ), Methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp), N- [1- (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene) ethyl (Dde ), 1- (4,4-dimethyl-2,6-dioxo-chlorohexylidene) -3-methylbutyl (ivDde), 1- (1-adamantyl) -1-methylethoxycarbonyl ( Adpoc), with preferred groups being Boc or Fmoc.

Representative examples of protecting groups for carboxyl groups are esters such as tert -butyl ester (tBu), allyl ester (All), triphenylmethyl ester (trityl ester, Trt), cyclohexyl ester (cHex), benzyl ester (Bzl) ), Ortho-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl ester, trimethylsilylethyl ester, 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), 4- (N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino) benzyl ester (Dmab). Preferred protecting groups of the invention are the All, tBu, cHex, Bzl and Trt esters.

Trifunctional amino acids can be protected with temporary or permanent protecting groups that are orthogonal to the protecting groups at the N- and C-terminus during the manufacturing process.

Guanidine groups in the arginine side chain are allyloxycarbonyl (Alloc), para-toluenesulfonyl (Tosyl, Tos), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 2,2 Or 4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), nitro or 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) group. Indole groups of the tryptophan side chain may be protected or unprotected with formyl (For), tert -butyloxycarbonyl (Boc), mesitylene-2-sulfonyl (Mts) groups. The hydroxyl group of the tyrosine side chain is 2-bromobenzyloxycarbonyl (2-BrZ), tert -butyl (tBu), allyl (All), benzyl (Bzl) or 2,6-dichlorobenzyl (2,6-diClZ ) Can be protected.

In a preferred embodiment, the protecting group strategy used is that the amino group is protected by Boc, the carboxyl group is protected by Bzl, cHex or All, the arginine side chain is protected by Tos, the tryptophan side chain is protected by For or Mts, and the tyrosine side chain Is a strategy protected with 2-BrZ or Bzl.

In another preferred embodiment, the protecting group strategy used is that the amino group is protected by Fmoc, the carboxyl group is protected by tBu, All or Trt, the arginine side chain is protected by Pbf or Pmc, and the tryptophan side chain is protected or unprotected by Boc And tyrosine side chains are protected with tBu.

Examples of such protecting groups and other additional protecting groups, their introduction and removal, can be found in the literature [Greene T.W. And P.G.M. Wuts (1999) "Protective groups in Organic Synthesis" John Wiley & Sons, New York, Atherton B. and Sheppard R.C. (1989) "Solid Phase Peptide Synthesis: A practical approach" IRL Oxford University Press. As used herein, the term "protecting group" is also meant to include polymer supports used for solid phase preparation.

If the synthesis takes place in whole or in part in the solid phase, the solid phase supports that can be used in the methods of the invention include polystyrene supports, polyethyleneglycols and analogs incorporated onto polystyrene, which allow simultaneous cleavage and deprotection of the peptide from the polymer support. P-methylbenzhydrylamine resin (MBHA) [Matsueda GR and Stewart JM (1981) "A p-methylbenzhydrylamine resin for improved solid phase preparation of peptide amides. improved solid phase synthesis of peptide amides) "Peptides 2: 45-50], 2-chlorotrityl resin [Barlos K., Gatos D., Kallitsis J., Papaphotiu G., Sotiriu P., Wenqing Y. and W. Schafer (1989) "Darstellung geschutzter Peptid substituierter Fragmente unter Einsatz Triphenylmethyl Harze" Tetrahedron Lett. 30: 3943-3946 ; Barlos K., Gatos D., Kapolos S., Papaphotiu G., Schafer W. and Wenqing Y. (1989) "Veresterung von partiell geschutzten Peptid fragment mit Harz. Einsatz von 2-Chlorotritylchlorid zur Synthese von Leu1-Gastrin I" Tetrahedron Lett. 30: 3947-3951], 5- (4-amino-3,5-dimethoxy-phenoxy) valeric acid that may or may not contain may contain a labile linker such as (PAL), and X tagel (TentaGel ^® ) Rapp Polymere GmbH, ChemMatrix ^® resins (Matrix Innovation, Inc) and analogs [Albericio F., Kneib Cordocier N., Biancalana S., Gera L., Masada RI, Hudson D., and Barany G. (1990) "5- (4- (9-fluorenylmethyloxycarbonyl) aminomethyl-3,5-dimethoxy-phenoxy) valeric acid for solid phase preparation of C-terminal peptide amide under mild conditions Preparation and application of the 5- (4- (9-fluorenylmethyloxycarbonyl) aminomethyl-3,5-dimethoxy-phenoxy) -valeric acid (PAL) handle for the solid phase synthesis of C-terminal peptide amides under mild conditions) "J. Org. Chem. 55: 3730-3743], 2- [4-aminomethyl (2,4-dimethoxyphenyl)] phenoxy acetic acid (AM) [Rink H. (1987) "Protected Peptide Fragments Using Diphenyl Trialkoxymethylester Resin Solid phase synthesis of protected peptide fragments using a diphenyl trialkoxy methylester resin "Tetrahedron Lett. 28: 3787-3790], Wang SS (1973) “p-alkoxybenzyl alcohol resins and p-alkoxybenzyloxycarbonylhydrazide resins (p-Alkoxybenzyl) used in the solid phase preparation of protective peptide fragments. Alcohol Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments) "J. Am. Chem. Soc. 95: 1328-1333 and the like, but are not limited to such.

Cosmetics  Or pharmaceutical compositions

The peptides of the present invention inhibit elastase activity and / or promote collagen synthesis in the skin, mucosa and / or scalp by any means capable of contacting the peptide to the site of action in a mammal, preferably a human body. It may be administered so as to, and in the form of a composition containing the peptide.

In this regard, another aspect of the present invention relates to a cosmetic or pharmaceutical composition comprising at least one of the peptides of Formula 1, stereoisomers thereof, mixtures thereof and / or to at least one cosmetic or pharmaceutically acceptable adjuvant Together is a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically acceptable salt thereof. Such compositions can be prepared by conventional methods known to those skilled in the art ["Harry's Cosmeticology", Eight Edition (2000) Rieger MM, ed., New York Chemical Pub, NY, US ; "Remington: The Sceince and Practice of Pharmacy", Twentieth Edition (2003) Gennaro AR, ed., Lippincott Williams & Wilkins, Philadelphia, US].

Peptides of the invention may vary in solubility in water depending on the nature of the sequence or the possibility of modifying the N-terminus and / or C-terminus. Therefore, the peptides of the present invention may be incorporated into the composition in the form of an aqueous solution, for example for cosmetics such as, but not limited to, ethanol, propanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or combinations thereof. Or in a water-insoluble form that can be dissolved in conventional pharmaceutically acceptable solvents.

As well as cosmetically or pharmaceutically effective amounts of the peptides of the invention to be administered, the dosage depends on a number of factors including age, the condition of the patient, the severity of the disorder or disease, the route and frequency of administration, and the nature of the peptide used. Will be different.

The term "cosmetic or pharmaceutically effective amount" means an amount of one or more nontoxic peptides sufficient to achieve the desired effect. The peptides of the present invention are used in cosmetic or pharmaceutical compositions of the present invention in cosmetic or pharmaceutically effective concentrations to achieve the desired effect, with a preferred form concentration relative to the total weight of the composition being from 0.00000001% to 20% by weight, It is preferably 0.000001% to 20% by weight, more preferably 0.0001% to 10% by weight, particularly preferably 0.0001% to 5% by weight.

The peptides of the invention can also be incorporated into cosmetic or pharmaceutical delivery systems and / or sustained release systems.

The term "delivery system" means a diluent, adjuvant, excipient or carrier with which the peptide of the invention is administered. Such cosmetic or pharmaceutical carriers may be liquids such as water, oils and surfactants, including petroleum, animal, vegetable or synthetic substances such as peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbate Sorbitan esters, ether sulfates, sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin This includes, but is not limited to. "Remington's Pharmaceutical Sciences" (E.W. Martin) describes diluents, adjuvants or excipients as suitable carriers.

The term "sustained release" is a term used in a conventional sense to mean a compound delivery system that allows a compound to be released slowly over a period of time, and preferably (but not necessarily) a compound is released constantly over a period of time. do.

Examples of delivery systems or sustained release systems include liposomes, mixed liposomes, oleosomes, niosomes, miniparticles, milliparticles, microparticles, nanoparticles and solid lipid nanoparticles, sponges, cyclodextrins, vesicles, micelles ), Mixed micelles of surfactants, surfactant-phospholipid mixed micelles, millispears, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, as well as microemulsions and nanoemulsions. It may be added to further enhance penetration and / or to improve pharmacokinetics and pharmacodynamics properties. Preferred delivery or sustained release systems are liposomes, surfactant-phospholipid mixed micelles and microemulsions, more preferably water in oil microemulsions with the internal structure of reverse micelles.

Sustained release systems can be prepared by methods known in the art, and compositions containing the same can be prepared, for example, by topical administration, including, for example, adhesive patches, non-tacky patches, and microelectric patches, or for example by oral route, Or by parenteral route such as, but not limited to, nasal, rectal or subcutaneous infusion or injection, or direct injection or injection into a particular body part, preferably It should be ensured that the peptide of the present invention is released in a relatively constant amount. The amount of peptide contained in the sustained release system will depend, for example, upon the site of administration, the duration and kinetics of release of the peptides of the invention, as well as the nature of the disease, disorder and / or condition desired to be treated and / or prevented.

In addition, the peptides of the present invention may be adsorbed onto solid organic polymers or solid inorganic substrates such as, but not limited to, talc, bentonite, silica, starch or maltodextrin.

 Compositions containing the peptides of the present invention may also be incorporated into fabrics, nonwovens, and medical means in direct contact with the skin, mucous membranes, and / or scalp, such that the anchoring system is biodegraded into fabrics, nonwovens, and medical means or with the body. The peptide can be released by friction, moisture in the body, pH of the skin or body temperature. Fabrics and nonwovens can also be used to make garments in direct contact with the body. Preferably, textiles, nonwovens and medical means containing the peptides of the present invention provide the benefits of promoting collagen synthesis and / or provide diseases, disorders and / or skin, mucous membranes and / or scalp resulting from elastase activity. Used to treat, prevent and / or manage disease.

Examples of woven, nonwoven, apparel, medical, and peptide immobilization means, including the delivery systems and / or sustained release systems described above, can be found in the literature and are known in the art [Schaab CK (1986)). "Impregnating Fabrics With Microcapsules", HAPPI May 1986 ; Nelson G. (2002) "Application of microencapsulation in textiles" Int. J. Pharm. 242, 55-62 ; "Biofunctional Textiles and the Skin" (2006) Curr. Probl. Dermatol. v. 33, Hipler UC and Elsner P., eds. S. Karger AG, Basel, Switzerland ; Malcom RK, McCullagh SD, Woolfson AD, Gorman SP, Johnes DS and Cuddy J. (2004) "Controlled release of a model antibacterial drug from self-lubricating silicone biomaterial) "J. Cont. Release 97, 313-320. Preferred fabrics, nonwovens, clothing and medical means include bandages, gauze, shirts, socks, stockings, underwear, girdle, gloves, diapers, sanitary napkins, dressings, bed spreads, handkerchiefs, hydrogels, adhesive patches, non-stick patches, microelectronic patches And / or facial masks.

A cosmetic or pharmaceutical composition containing a peptide of the invention, its stereoisomers, mixtures thereof, or cosmetic or pharmaceutically acceptable salts may comprise any cosmetically or pharmaceutically acceptable excipients necessary for the preparation of the desired dosage form. It can be used in several types of topical or transdermal compositions optionally containing [Fauli i Trillo C. (1993) Treatise on Galenic Pharmarcy, Luzan 5, SA Ediciones, Madrid].

Topical or transdermal compositions may also take the form of solid, liquid or semi-solid dosage forms, such as but not limited to creams, and multiple emulsions, such as oil in water and / or silicone emulsions, oils and Water emulsion in water, water / oil / water or water / silicone / water emulsion, and oil / water / oil or silicone / water / silica emulsion; Anhydrous compositions, aqueous dispersions, oils, milk, balms, foams, lotions, gels, cream gels, water alcohol solutions, hydroglycol solutions, hydrogels, liniments, ceras, soaps, shampoos, conditioners, serums, polysaccharide films , Ointment, mousse, pomade, powder, bar, pencil, spray or aerosol (spray) (including, but not limited to, "non-rinsing" compositions and "rinsing" compositions) have. Such topical or transdermal compositions are prepared by techniques known in the art, for example, but not limited to, handkerchiefs, hydrogels, tacky patches, non-tacky patches, microelectric patches, or face masks, including but not limited to It can also be incorporated into accessories, such as makeup foundations such as liquid foundations and compact foundations, makeup removal lotions, makeup removal milks, concealers, eye shadows, lipsticks, lip protectors, lip gloss and powders. Can be.

The cosmetic or pharmaceutical composition of the present invention may additionally contain substances that enhance the percutaneous absorption of the peptides of the present invention, such materials include, for example, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, interfacial Active agents, azone (1-dodecylazacycloheptan-2-one), alcohols, urea, ethoxydiglycol, acetone, propylene glycol or polyethylene glycol, and the like. In addition, the cosmetic or pharmaceutical composition of the present invention may be used to improve the penetration of the peptide of the present invention, such as iontophoresis, ultrasonography, electroporation, mechanical pressure, osmotic pressure gradient, closure therapy, microinjection or oxygen injection. It may be administered to a topical area to be treated via a topical or transdermal route by syringeless pressurized infusion, microelectric patches, or a combination thereof. The site of administration will be determined by the nature of the disease, disorder and / or condition desired to be prevented, managed and / or treated.

In addition, the cosmetic composition containing the peptide of the present invention, its stereoisomers and / or cosmetic or pharmaceutically acceptable salts can be used in various forms of oral compositions. Preferred oral cosmetic forms include, for example, capsules including gelatin capsules, tablets including dragees, powders, granules, chewing gums, solutions, suspensions, emulsions, syrups, polysaccharide films, jelly or gelatin and other forms known in the art, and the like. There is, but is not limited to: In particular, the peptides of the present invention may be incorporated into functional foods or fortified foods, for example in the form of diet bars or compressed powders or uncompressed powders. These powders can be dissolved in water, beverages, dairy products, soy derivatives, or incorporated into diet bars. Peptides of the invention may be formulated with conventional excipients and auxiliaries used in oral compositions or food supplements, examples of which are fatty ingredients, aqueous ingredients, diluents, preservatives, texturizing agents commonly used in the food industry. agents), flavors, aromas, antioxidants and food colorings, but are not limited thereto.

The cosmetic compositions containing the peptides of the invention, their stereoisomers and / or cosmetic or pharmaceutically acceptable salts may also be used by topical or transdermal routes, by other suitable methods, for example orally or parenterally. It may be administered by a route and will contain pharmaceutically acceptable excipients which are essential for the preparation of the desired dosage form. As used herein, the term “parenteral” refers to the nose, ear, eye, rectal route, subcutaneous, intradermal, intravascular injection, eg, intravenous, intramuscular, intravitreous, intravertebral, intracranial. (intracranial), intraarticular, intrathecal and intraperitoneal injections, as well as any similar injection or infusion techniques. Techniques for the various pharmaceutical dosage forms of excipients necessary for obtaining the active ingredient and the desired dosage form can be found in, for example, "Tratado de Farmacia Galencia" (C. Fauli i Trillo, 1993, Luzan 5, SA Ediciones, Madrid). Can be.

Additional ingredients commonly used in compositions for the treatment of skin, mucous membranes and / or scalp in cosmetic or pharmaceutically acceptable adjuvants incorporated into the cosmetic or pharmaceutical compositions of the invention, for example other elastase inhibitors, matrix metals Roproteinase inhibitors, promoting or inhibiting melanin synthesis, whitening or bleaching agents, propigmenting agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5-α-reductase inhibitors, lysyl- and And / or propyl-hydroxylase inhibitors, antioxidants, free radical scavengers and / or air pollution inhibitors, reactive carbonyl species scavengers, anti-glycosyls, antihistamines, anti-emetics, antiviral agents, insect repellents, emulsifiers, emollients, organic solvents, Liquid propellants, skin conditioners such as humectants, moisture retaining substances, alpha hydroxy phase, beta hydroxy acids, humectants, epithelial Degrading enzymes, vitamins, pigments or colorants, dyes, gelling polymers, thickeners, surfactants, emollients, anti-wrinkle agents, reducing or treating sagging eyes, exfoliants, antibacterial agents, antifungal agents, fungicides, fungicides, bacteriostatic agents, Substances capable of promoting the synthesis of dermal or epidermal polymers and / or inhibiting or preventing the degradation of the molecules, such as collagen synthesis promoters, elastin synthesis promoters, decorin synthesis promoters, laminin synthesis promoters, defesin synthesis promoters, sha Ferong Synthesis Accelerator, Aquaporin Synthesis Accelerator, Hyaluronic Acid Synthesis Accelerator, Fibronectin Synthesis Accelerator, Sirtuin Synthesis Accelerator, Lipid and Keratin Component (Ceramide, Fatty Acid, etc.) Synthesis Accelerator, Collagen Degradation Inhibitor, Other Elastin Degradation Inhibitor, Cathepsin G and Such as serine protease inhibitors, keratinocyte growth promoters, and adiposite growth Agent, melanocyte growth promoter, keratinocyte differentiation promoter, adiposite differentiation promoter, acetylcholinesterase inhibitor, skin relaxant, glycosaminoglycan synthesis promoter, hyperkeratosis preventive agent, comedolytic agent, anti psoriasis Agents, DNA repair agents, DNA protectors, stabilizers, itch inhibitors, sensitive skin treatment and / or care agents, hardeners, stretch mark inhibitors, binders, sebum production regulators, lipolytic or lipolytic accelerators, anti-cellulite agents, antiperspirants , Recovery promoters, recovery co-adjuvant, re-epithelialization promoter, re-epithelial co-adjuvant, cytokine growth factor, sedative, anti-inflammatory, anesthetic, capillary and / or microcirculatory agents, neovascularization agents, vascular permeability inhibitors, Anti-edema, cell metabolism agent, dermal-epidermal binding enhancer, hair growth inducer, hair growth inhibition Or retardants, preservatives, fragrances, chelating agents, vegetable extracts, essential oils, seaweed extracts, substances obtained in the process of biofermentation, natural salts, cell extracts and sunscreens (organic or mineral light against ultraviolet A and / or B). Protective agents) and the like, and this additional component should be able to be used physically and chemically in combination with other components of the composition, in particular the peptide of formula 1 contained in the composition of the present invention. In addition, the nature of these additional components should not be altered to an unacceptable degree of benefit of the peptides of the present invention. The nature of these additional ingredients may be synthetic or natural as plant extracts, or may be obtained by a biofermentation process. Techniques for further examples can be found in the CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).

An additional aspect of the present invention comprises a cosmetic or pharmaceutically effective amount of at least one peptide, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts thereof of the present invention, and elaster A cosmetic or pharmaceutical composition containing a cosmetically or pharmaceutically effective amount of at least one synthetic compound, a natural extract, or a biofermentation process, which is an agent for inhibiting an agent, and for example Pentapharm / Elhibin ^® [INCI: glycine soybean (soybean) protein] commercially available from DMS, Preregen ^® [INCI: glycine soybean (soybean) protein, oxidoreductase] or Regu ^® -Age [INCI: hydrolyzed rice bran protein, glycine Soybean (soybean) protein, oxidoreductase] ; Juvenesce [INCI: ethoxydiglycol and caprylic triglycerides, retinol, ursolic acid, phytonadione, ilomasat], available from Coletica / Engelhard / BASF, Micromerol ^® [INCI: apple extract], Heather Extract [INCI: Kaluga or vulgaris extract], Extracellium ^® [INCI: hydrolyzed potato protein or ^{Flavagrum TM PEG [INCI: PEG-} 6 isostearate, Hess Ferre tin dilaurate; Laboratories Serobioloiques / Proteasyl ^®, available from Cognis [INCI: pea extract; Sepilift DPHP [INCI: dipalmitoyl hydroxyproline] sold by SEPPIC ; Vitaderm ^® [INCI: alcohol, water, glycerin, hydrolyzed rice protein, Ilex Aquifolium extract, sodium ursolate, sodium oleanolate] available from Rahn ; Gatulin ^® Age Defense 2, available from Gattefoss [INCI: Walnut (Walnut) Seed Extract; IP2000 [INCI: dextrin, trifluoroacetyl tripeptide-2] available from IEB and Atrium ; Radicaptol commercially available from Solaabia [INCI: propylene glycol, water, Passiflora Incarnata flower extract, black hydrangea (black currant) leaf extract, vine leaf extract] ; Or ViaPure ^® available from Soliance [INCI: Oliva num (Indian Frankincense) Extract], etc., but is not limited to this.

An additional aspect of the present invention comprises a cosmetic or pharmaceutically effective amount of at least one peptide of the present invention, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, and also promotes collagen synthesis promoter. A cosmetic or pharmaceutical composition containing at least one synthetic compound, a natural extract or a substance obtained by a biofermentation process, in a cosmetic or pharmaceutically effective amount, and examples of such collagen synthesis promoter materials include ascorbic acid and its Derivatives (e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate and ascorbyl alpha- and beta-glucosides), retinol and derivatives thereof (e.g. retinoic acid, retinal, retinyl acetate or Retinyl palmitate), for example aloe and centella (Cente) lla) Botanical extracts, such as extracts of species, carnitine, carnosine, creatine, asiatic acid, madecassic acid, madecassoside, asiaticoside, centella asiatica extract, niacinamide, astaxanthin, Glycans, soy extracts and soy isoflavones such as genistein and dyedzein, rutin, chrysine, maline, betel nut alkaloids, paulscholine, betulinic acid, plantago species, TGF Beta, ginkgo extract, glutamine and glycolic acid, Matrixyl ^® [INCI: palmitoyl pentapeptide-4], Matrixyl 3000 ^® [INCI: palmitoyl tetrapeptide-7, palmitoyl oligopeptide] or Dermaxyl available from Sederma / Croda ^® [INCI: C12-C15 alkyl benzoate, tribehenin, ceramide 2, PEG 10 rapeseed sterol, palmitoyl oligopeptide] ; Syn ^® -Coll [INCI: palmitoyl tripeptide-5], Phytaluronate ^® [INCI: locust bean gum] or BeauActive ^™ MTP [INCI: hydrolyzed milk protein] available from Pentapharm / DSM ; Thalassine ^™ [INCI: seaweed extract] commercially available from Biotechmarine ; EquiStat ^™ [INCI: apple extract, glycine soy protein] or Juvenesce [INCI: ethoxydiglycol and caprylic triglycerides, retinol, ursolic acid, phytonadione, ilomasat] available from Coletica / Engelhard / BASF ; SMS Anti-wrinkle ^® sold by Silab [INCI: Sugar apple an oligopeptide purified from (Annona Squamosa)] or Papilactyl D ^® [INCI: Water, Cyprus S. particulate reontu's tyubeo (Cyperus Esculentus Tuber) extract; ChroNOline ^TM [INCI: glycerin, water, dextrin, caprooil tetrapeptide-3], Kollaren ^® [INCI: tripeptide-1] or Thymulen ^® [INCI: water, dextran, acetyl tetra, commercially available from the Atrium Innovations / Unipex Group Peptide-2] ; Available from Solabia BioLyse TA [INCI: original oligopeptide composed of L- lysine and L- arginine or Peptiskin ^® [INCI: arginine / lysine polypeptide; Gatulin ^® [INCI: Caprylic / Capric Triglycerides, Spilanthes Acmella Flower Extract], available from Gattefosse ; PhytoCellTec ^™ Malus Domestica sold by Mibelle Biochemistry (INCI: Malus Domestica fruit cell culture, xanthan gum, glycerin, lecithin, phenoxyethanol, water) ; Phytosphingosine SLC sold by Evonik Goldschmidt [INCI: Salicyloyl Phytospinosine] ; Dakaline [INCI: Prunus Amygdalus Dulcis, Anogeisssus Leioccarpus Bark Extract] sold by Soliance ; Collaxyl ^® available from Vincience [INCI: hexapeptides -9], GP4G [INCI: Arte mia (Artemia) Extract], D'Orientine ^TM [INCI: said date palm tree extract or Ederline ^TM [INCI: apple extract; Or Homeostatine (INCI: Enteromorpha Compressa, Casalpinia Spinosa) available from Provital.

An additional aspect of the present invention comprises a cosmetically or pharmaceutically effective amount of at least one peptide, stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts of the present invention, and also comprises a reactive carbo A cosmetic or pharmaceutical composition containing at least one synthetic compound, a natural extract or a substance obtained by a biofermentation process, which is a niel species remover, a free radical remover and / or an anti-glycosylating agent, in a cosmetic or pharmaceutical composition, the reactive carbonyl species Examples of scavengers, free radical scavengers and / or anti-glycosylating agents include carnosine and derivatives thereof, GHK [INCI: tripeptide-1] and salts and / or derivatives thereof, or Aldenine ^® [INCI: hydrolyzed wheat protein, Hydrolyzed soy protein, tripeptide-1] or Preventhelia ^™ [INCI: diaminopropionyl available from Lipotec Tripeptide-33], but is not limited thereto.

An additional aspect of the present invention comprises a cosmetic or pharmaceutically effective amount of at least one peptide of the present invention, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, and furthermore And / or to a cosmetic or pharmaceutical composition containing at least one extract as an anti-aging agent or at least one anti-wrinkle and / or synthetic compound or product as an anti-aging agent in a cosmetic or pharmaceutical effective amount, wherein the anti-wrinkle and / or Examples of antioxidant extracts include Vitis vinifera, Rosa canina, Curcuma longa, Iris pallida, Theobroma cacao, Ginkgo biloba, Edelweiss (Leontopodium alpinum), or extracts of Dunaliella salina, etc., the anti-wrinkle agent or furnace Examples of inhibitors of synthetic compounds or products, Sederma / Croda Matrixyl available from ^® [INCI: palmitoyl pentapeptide ^{-3], Matrixyl 3000 ® [INCI} : palmitoyl tetrapeptide-7, palmitoyl oligopeptide], Essenskin ^TM [INCI: calcium hydroxy methionine], Renovage [INCI: teprenone or Dermaxyl ^® [INCI: palmitoyl oligopeptide; Vialox ^® available from Pentapharm / DSM [INCI: pentapeptide ^{-3], Syn Ake ® [INCI} : Dipeptide dia one benzylamide as diamino butyric diacetate], Syn ^® -Coll [INCI: palmitoyl tripeptide -5; , Phytaluronate ^® [INCI: locust bean gum] or Preregen ^® [INCI: glycine bean (soybean) protein, oxidoreductase] ; Myoxinol ^™ [INCI: hydrolyzed Hibiscus Esculentus extract] available from Laboratories Serobioloiques / Cognis, Syniorage ^™ [INCI: acetyl tetrapeptide-11], Dermican ^™ [INCI: acetyl tetrapeptide-9] or DN -AGE ^™ [INCI: Cassia Alata Leaf Extract] ; Algisum C ^® [INCI: methylsilanol mannuronate] or Hydroxyprolisilane CN ^® [INCI: methylsilanol hydroxyproline maspartate] available from Exsymol ; Argireline ^® [INCI: acetyl hexapeptide-8], SNAP-7 [INCI: acetyl heptapeptide-4], SNAP-8 [INCI: acetyl octapeptide-3], Leuphasyl ^® [INCI: pentapeptide- commercially available from Lipotec 18], Inyline ^TM [INCI: acetyl hexapeptide-30 (proposed), Aldenine ^® [INCI: hydrolyzed wheat protein, hydrolyzed soy protein, tripeptide-1], Preventhelia ^TM [INCI: diaminopropionyl tripeptide-33], Decorinyl ^TM [INCI: tripeptide-10 citrulline], Trylagen ^TM [INCI: Pseudoaltermonas fermented extract, hydrolyzed wheat protein, hydrolyzed soy protein, Tripeptide-10 citrulline, tripeptide-1], Eyeseryl® [INCI: acetyl tetrapeptide-5], Peptide AC29 [INCI: acetyl tripeptide-30 citrulline], Lipochroman-6 [INCI: dimethylmethoxy chromamanol], Chromabright ^TM [INCI: Dimethylmethoxy Chromylyl Palmitate], Vilastene ^TM [INCI: Lysine HCl, Lecithin, Tripeptide-10 Citrulline], dGlyAGE ^TM [INCI: Lysine HCl, Lecithin, Tripeptide-9 Citrulline] or Antarcticine® [INCI: Pseudo-Altermonas Fermented Extract] ; Kollaren ^® [INCI: Tripeptide-1, Dextran], available from Institut Europeen de Biologie Cellulaire ; Collaxyl ^® [INCI: Hexapeptide-9], Orsirtine ^TM GL [INCI: Oryza Sativa Extract], available from Vincience, D'Orientine ^TM IS [INCI: date palm seed extract], Phytoquitescine ^™ [INCI: Triticum monococcum extract] or Quintescine ^™ IS [INCI: dipeptide-4] ; BONT-L Peptide [INCI: palmitoyl hexapeptide-19] available from Infinitec Activos ; Deepaline ^TM available from Seppic PVB [INCI: Palmitoyl Hydrolysed Wheat Protein] or Sepilift ^® DPHP [INCI: dipalmitoyl hydroxyproline]; Gatulin ^® Expression [INCI: Acmella Oleracea extract] available from Gattefosse, Gatulin ^® In-Tense [INCI: Spilanthes Acmella flower extract] or Gatulin ^® Age Defense 2 [INCI: Walnut seed extract ; Thalassine ^™ [INCI: seaweed extract] commercially available from Biotechmarine ; ChroNOline ^™ [INCI: caprooil tetrapeptide-3] or Thymulen-4 [INCI: acetyl tetrapeptide-2] available from Atrium Innovations / Unipex Group ; EquiStat ^™ [INCI: apple extract, glycine soy protein] or Juvenesce [INCI: ethoxydiglycol and caprylic triglycerides, retinol, ursolic acid, phytonadione, ilomasat] available from Coletica / Engelhard / BASF ; Ameliox [INCI: carnosine, tocopherol, Silybum Marianum fruit extract] or PhytoCellTec Malus Domestica [INCI: Malus Domestica fruit cell culture medium] available from Mibelle Biochemistry ; Bioxilift available from Silab [INCI: Pim Piniella no breath (Pimpinella Anisum) extract] or SMS Anti-wrinkle ^® [INCI: Sugar apple (Annona Squamosa) Seed Extract], Ca ^{2 +} channel blocker, for example, Al suberic, manganese Or magnesium salts, certain secondary or tertiary amines, retinol and derivatives thereof, idebenone and derivatives thereof, coenzyme Q10 and derivatives thereof, boswellic acids and derivatives thereof, GHK and derivatives and / or salts, carnosine And derivatives thereof such as, but not limited to, portolase or DNA repair enzymes such as T4 endonuclease V, or chloride channel antagonists.

An additional aspect of the present invention comprises a cosmetically or pharmaceutically effective amount of at least one peptide of the present invention, stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts, and furthermore, cellulite At least one synthetic or natural extract that is an inhibitor, lipolytic and / or anti-edema, or additionally, at least one synthetic compound, extract or biofermentation process that is an anti-cellulite, lipolytic and / or anti-edema Or to a cosmetic or pharmaceutical composition containing a pharmaceutically effective amount, wherein the anti-cellulite, lipolytic and / or anti-edema synthetic or natural extracts, for example, Bupleurum Chinensis, Secropia Cecropia Obtusifolia, Celosia Cristat, Tela Asiatica, Chenopodium Quinoa, Chrysanthellun Indicum, Citrus Aurantium Amara, Coffee Arabica, Coleus Forskohlii, Comifola Commiphora Myrrha, Chrithmum Maritimum, Eugenia Caryophyllus, Ginkgo, Ivy Extract, Hibiscus sabdariffa, Ilex Aquifolium, La Laminaria Digitata, Nelumbium Speciosum, Paulinia Cupana, Peumus Boldus, Phyllacantha Fibrosa, Prunella Bulgaris, Prunus Amygdalus Dulcis, Rucus Aculeatus (Bircher's Broome Extract), Sambucus Nigra, Spirulina Platensis Egg Spirulina Platensis Algae, Uncaria Tomentosa or Verbena Officinalis, and the like, and the anti-cellulite, lipolytic and / or anti- Examples of synthetic compounds that are edema, extracts, or substances obtained by biofermentation processes include, for example, Regu ^® -Shape sold by Dihydromyricetin, Coenzyme A, Lipase, Glausin, Esculin, Bisnadine, Pentapharm / DSM [ INCI: isomerized linoleic acid, lecithin, glycerin, polysorbate 80] ; UCPeptide ^™ V [INCI: pentapeptide] or AT Peptide ^™ [INCI: tripeptide-3] available from Vincience / ISP ; Adiposlim [INCI: sorbitan laurate, lauroyl proline] available from SEPPIC ; Liporeductyl ^® [INCI: Lecithin, Caffeine, Rucuscus Aculeatus Root Extract, T-Hydroidoids, Gentian Extract, Carnitine, Escin, Tripeptide-1] available from Lipotec, Caffeine, Carnitine, S Cinna and / or iodide triethanolamine, and the like.

Usage

Another feature of the invention is the preparation of a cosmetic or pharmaceutical composition for the treatment and / or care of skin, mucous membranes and / or scalp, wherein at least one peptide of the peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics And to the use of pharmaceutically acceptable salts.

Furthermore, preferably. The present invention relates to the preparation of a cosmetic or pharmaceutical composition for inhibiting elastase and / or promoting collagen synthesis in the skin, mucous membranes and / or scalp, wherein at least one peptide of the peptide of formula 1, stereoisomers thereof, mixtures thereof And / or to use cosmetically or pharmaceutically acceptable salts.

Also, preferably, another aspect of the present invention provides an advantage of promoting collagen synthesis in the skin, mucous membranes and / or scalp and / or disease of the skin, mucous membranes and / or scalp resulting from elastase activity, In the preparation of a cosmetic or pharmaceutical composition for treating, preventing and / or managing a disorder and / or disease, at least one peptide of the peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceutically It relates to the use of acceptable salts.

Preferably, diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp that are to be treated, prevented and / or managed due to elastase activity which provide the benefit of promoting collagen synthesis include wrinkles, impression wrinkles and stretch marks. , Skin aging, skin photoaging, wound healing disorders, ulcers, diabetic ulcers, keloids, hypertrophic scars, acne, cellulite, orange skin, elastic tissue atrophy, elastic fibrosis, keratosis, inflammation, dermatitis, atopic dermatitis, allergic Contact dermatitis, sensitive skin, eczema, bullous swelling, gingivitis, periodontitis, skin cancer, tumor infiltration, tumor metastasis, capillary dilatation, coupersis, varicose veins, periscopic dark circles, drooping eyes, hair loss and hair damage, Injections and / or psoriasis.

According to a preferred embodiment, the present invention provides the use of a peptide of formula 1 in the preparation of a cosmetic or pharmaceutical composition for treating skin, mucous membranes and / or scalp for reducing, delaying and / or preventing signs of aging and / or photoaging. It's about things.

According to another preferred embodiment, the invention provides for the preparation of cosmetic or pharmaceutical compositions which increase the elasticity of the skin, mucous membranes and / or scalp, at least one of the peptides of formula 1, stereoisomers thereof, mixtures thereof and / or Or to the use of cosmetic or pharmaceutically acceptable salts.

In another aspect, the present invention provides a pharmaceutical or pharmaceutical composition for reducing or eliminating facial wrinkles, comprising: at least one peptide of the peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceuticals To an acceptable salt.

According to another preferred embodiment, the present invention provides at least one of the peptide of formula 1 in the preparation of a cosmetic or pharmaceutical composition for hair treatment or hair hygiene, including a shampoo, conditioner, hair lotion, hair tonic, or scalp mask To peptides, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts thereof. Examples of cosmetic or pharmaceutical compositions for hair treatment or hair hygiene include shampoos, conditioners, hair lotions, hair tonics or masks for the scalp.

According to another preferred embodiment, the invention relates to the preparation of a cosmetic or pharmaceutical composition for the treatment and / or care of the skin of the face and / or the body or for the hygiene of the body, at least one peptide of the peptide of formula 1, stereoisomers thereof , And mixtures thereof and / or the use of cosmetic or pharmaceutically acceptable salts. Cosmetic or pharmaceutical compositions for the treatment and / or care of the skin of the face and / or body or for body hygiene include, for example, creams, multiple emulsions such as oil in water and / or silicone emulsions, water emulsions in oil and / or silicone, Water / oil / water or water / silicone / water emulsion, and oil / water / oil or silicone / water / silica emulsion; Anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels, water alcohol solutions, hydroglycol solutions, hydrogels, application potions, ceras, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, Mousse, pomade, powder, bar, pencil, spray or aerosol (spray) (including "non-rinse" formulations and "rinse" formulations), handkerchiefs, hydrogels, tacky patches, non-tacky patches, Microelectric patches or face masks, makeup foundations such as, but not limited to, liquid foundations and compact foundations, makeup removal lotions, makeup removal milks, concealers, eye shadows, lipsticks, lip protectors, lip gloss and powders It includes.

Compositions containing peptides, stereoisomers thereof, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof of the present invention may be used for the treatment of, preventing, and / or managing diseases, disorders and / or diseases, including, It may be applied to mucous membranes and / or scalp and may be administered orally or parenterally as needed.

Cosmetic or pharmaceutical compositions in connection with the present invention may be applied to a syringe such as injection by iontophoresis, ultrasonography, electroporation, mechanical pressure, osmotic pressure gradient, occlusion therapy, microinjection or oxygen pressure to enhance penetration of the peptides of the present invention. And may be applied to the skin and / or scalp by pressure injection, or a combination thereof.

Another aspect of the invention provides cosmetics for treating, preventing and / or managing diseases, disorders and / or diseases of a mammal, preferably a human, which provides the advantage of inhibiting elastase and / or promoting collagen synthesis. Pharmaceutical method, comprising a cosmetic or pharmaceutically effective amount of at least one peptide of formula (1), stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, preferably comprising Or it relates to a method comprising the step of administering in the form of a pharmaceutical composition. Also preferably, the present invention provides cosmetic or pharmaceutical methods for enhancing the elasticity of the skin, mucous membranes and / or scalp. Another aspect of the invention relates to a cosmetic or pharmaceutical method for reducing or eliminating facial wrinkles.

The present invention also provides cosmetics for the benefit of promoting collagen synthesis and / or for treating, preventing and / or managing diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp due to elastase activity. As a pharmaceutical method, a cosmetic or pharmaceutical composition containing at least one peptide, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts of the peptides of the invention may be applied to the skin, mucosa and / or scalp. It provides a method comprising the step of topical or transdermal application or oral or parenteral administration to.

The frequency of application or administration can vary greatly depending on the needs of each subject, with a recommended range of application or administration levels ranging from once a month to 10 times a day, preferably once a week to 4 days a day. Times, more preferably three times a week to three times a day, particularly preferably once or twice a day.

The following examples provided herein specifically illustrate the nature of the present invention. The examples are only intended to illustrate the purpose of the invention and should not be construed as limiting the scope of the invention.

Example

General methodology

All agents and solvents are synthetic and are used without further processing.

Abbreviation

The abbreviation used for amino acids is Eur. J. Biochem. (1984) 138: 9-37 and J. Biol. Chem. (1989) in accordance with the provisions of the Commission on Biochemical Nomenclature of IUPAC-IUB as set forth in 264: 633-673.

®, resin; Ac, acetyl; Adpoc, 1- (1-adamantyl) -1-methylethoxy-carbonyl; Ala, alanine; All, allyl; Alloc, allyloxycarbonyl; AM, 2- [4-aminomethyl- (2,4-dimethoxyphenyl)] phenoxyacetic acid; Arg, arginine; Boc, tert -butyloxycarbonyl; 2-BrZ, 2-bromobenzyloxycarbonyl; BSA, bovine seralbumin; Bzl, benzyl; Cbz, benzyloxycarbonyl; cHx, cyclohexyl; Cit, citrulline; ClTrt-®, 2-chlorotrityl resin; ClZ, 2-chlorobenzyl; cps, centipoise; C-terminus, carboxy terminus; DCM, dichloromethane; Dde, N- [1- (4,4-dimethyl-2,6-dioxochlorohex-1-ylidene) ethyl; 2,6-diCIZ, 2,6-dichlorobenzyloxycarbonyl; DIEA, N, N-diisopropylethyl amine; DIPCDI, N, N'-diisopropylcarbodiimide; Dmab, 4- (N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino) benzyl; DMF, N, N-dimethylformamide; DMSO, dimethyl sulfoxide; DNP, 2,4-dinitrophenyl; DPPC, dipalmitoylphosphadidylcholine; ECM, extracellular matrix; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; equiv, equivalents; ES-MS, electrospray ion mass spectrometry; Fm, fluorenylmethyl; Fmoc, 9-fluorenylmethyloxycarbonyl; GAG, glycosaminoglycans; Gly, glycine; HLE, human leukocyte elastase; HOBt, 1-hydroxybenzotriazole; HPLC, high performance liquid chromatography; INCI, international cosmetics naming; ivDde, 1- (4,4-dimethyl-2,6-dioxo-cyclohexylidene) -3-methyl-butyl; MAGP, microfibrils-binding glycoproteins; MBHA, p-methylbenzhydrylamine; MeCN, acetonitrile; MeOH, methanol; MLV, multilayer vesicles; MMP, matrix metalloproteinases; Mtr, 4-methoxy-2,3,6-trimethylbenzenesulfonyl; Mtt, methyltrityl or methoxytrityl; Nle, norleucine; N-terminus, amino terminus; PAL, 5- (4- (aminomethyl) -3,5-bis (methoxy) phenoxy) valeric acid; Palm, palmitoyl; Pbf, 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl; PBS, phosphate buffer salts; Phg, phenyl glycine; Pmc, 2,2,5,7,8-pentamethylchroman-6-sulfonyl; pNZ, para-nitrobenzyloxycarbonyl; qs, sufficient amount; qsp, until enough; tBu, tert -butyl; Teoc, 2- (trimethylsilyl) ethyloxycarbonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TIS, triisopropylsilane; Tos, para-toluenesulfonyl or tosyl; Troc, 2,2,2-trichloroethoxycarbonyl; Trp, tryptophan; Trt, triphenylmethyl or trityl; Tyr, tyrosine; ULV, single thin film vesicles; UV, ultraviolet light; Val, valine; Z, benzyloxycarbonyl.

Chemical manufacturing

All preparation is carried out in a Pyrex ^® reactor equipped with a polypropylene syringe or a porous plate equipped with a disc of porous polyethylene. Solvent and water soluble reactants are removed by suction. Fmoc groups are removed with piperidine-DMF (2: 8, v / v) (1 × 1 min, 1 × 5 min, 5 mL / g resin) [Lloyd Williams P., Albericio F. and Giralt E. (1997). ) "Chemical Approached to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA. Washing between the deprotection, binding and again deprotection steps was performed in DMF (3 × 1 min) with 10 mL solvent / g resin per run. The coupling reaction was performed with 3 mL solvent / g resin. Binding control was achieved by a ninhydrin test [Kaiser E., Colescott RL, Bossing CD and Cook PI (1970) "Color test for detection of free terminal amino groups in solid peptide preparation. amino groups in the solid phase synthesis of peptides) "Anal. Biochem. 34: 595-598. All preparation reactions and washes were performed at room temperature.

HPLC chromatographic analysis was performed with a Shimadzu eqipment (Kyoto, Japan) using a reverse-phase column (250 × 4.0 mm, Kromasil C ₈ , 5 μm, Akzo Nobel, Sweden) thermostatically controlled at 30 ° C. It was. Elution was performed using an acetonitrile (+ 0.07% TFA) gradient in water (+ 0.1% TFA) at a flow rate of 1 mL / min and detection was performed at 220 nm.

Fmoc - Xn - AA _One - AA ₂ - AA ₃ - AA ₄ - Ym -O-2- CITrT To obtain -®, wherein AA ₄ Is -L-Phg-, -D- Phg - or - Gly -ego; AA ₃ -L- Trp -, -L- Tyr -Or -L- Val -; AA ₂ Is -L-Ala-, -L- Cit -, -L- Nle -, -L- Phg -Or-D- Phg -ego; AA _One -L- Arg -, -L- Phg -, -D-Phg- or -L- Nle -; n and m are zero.

3.29 g of Fmoc-L-Phg-OH, 3.29 g of Fmoc-D-Phg-OH, or 2.61 g of Fmoc-Gly-OH (8.8 mmol; 1 equivalent) is dissolved in 55 ml of DCM, and 1.3 ml is added thereto. DIEA (7.6 mmol; 0.86 equiv) was added and bound to dry 2-chlorotrityl resin (5.5 g; 8.8 mmol). The suspension was stirred for 5 minutes and then 2.5 ml of DIEA (14.6 mmol; 1.66 equiv) was added. The mixture was allowed to react for 40 minutes. The remaining chloride group was blocked by treatment with 4.4 mL of MeOH.

Deprotect the Fmoc N-terminal group as described in the above general method, and use DIMFDI (3.39 mL, 22 mmol, 2.5 equiv) and HOBt (3.37 g, 22 mmol, 2.5 equiv) for 1 hour using DMF as solvent Bound to peptidyl resin. This resin was then washed as described in the general method and the subsequent amino acid was bound by repeating the deprotection treatment of the Fmoc group. According to the procedure described above, 6.85 g of Fmoc-L-Ala-OH, 8.74 g, in turn, in the presence of 3.37 g HOBt (22 mmol, 2.5 equiv) and 3.39 mL DIPCDI (22 mmol, 2.5 equiv) for each binding Fmoc-L-Cit-OH, 7.77 g Fmoc-L-Nle-OH, 8.21 g Fmoc-L-Phg-OH or 8.21 g Fmoc-D-Phg-OH (22 mmol, 2.5 equiv) and then 14.27 g Fmoc-L-Arg- (Pbf) -OH, 8.21 g Fmoc-L-Phg-OH, 8.21 g Fmoc-D-Phg-OH or 7.77 g Fmoc-L-Nle-OH (22 mmol, 2.5 equivalents) was combined.

After preparation, the peptidyl resin was washed with DCM (5 × 3 min) and then dried by nitrogen flow.

Fmoc - Xn - AA _One - AA ₂ - AA ₃ - AA ₄ - Ym - AM - MBHA Obtaining -®, wherein AA ₄ Is -L- Phg -, -D-Phg- or- Gly -ego; AA ₃ -L- Trp -, -L- Tyr -Or -L- Val -; AA ₂ Is -L-Ala-, -L- Cit -, -L- Nle -, -L- Phg -Or-D- Phg -ego; AA _One -L- Arg -, -L- Phg -, -D-Phg- or -L- Nle -; n and m are zero.

6.85 g of Fmoc-AM-MBHA (5 mmol) with a load of 0.73 mmol / g was removed by treatment with piperidine-DMF according to the general procedure described above. 9.33 g of Fmoc-L-Phg-OH in this deprotected resin in the presence of DIPCDI (3.85 mL, 25 mmol; 5 equiv) and HOBt (3.85 g, 25 mmol; 5 equiv) for 1 h using DMF as solvent , 9.33 g of Fmoc-D-Phg-OH or 7.43 g of Fmoc-Gly-OH (25 mmol; 5 equivalents) was incorporated.

 This resin was then washed as described in the general method above and subsequent amino acid was bound by repeating the deprotection treatment of the Fmoc group. According to the procedure described above, 10.67 g of Fmoc-L-Trp-OH, 11.49 g of Fmoc in the presence of 3.85 g of HOBt (25 mmol; 5 equivalents) and 3.85 mL of DIPCDI (25 mmol; 5 equivalents) for each binding -L-Tyr- (tBu) -OH or 8.49 g of Fmoc-L-Val-OH (25 mmol, 5 equiv); 9.33 g Fmoc-L-Phg-OH, 9.33 g Fmoc-D-Phg-OH, 7.78 g Fmoc-L-Ala-OH, 9.94 g Fmoc-L-Cit-OH or 8.84 g Fmoc-L -Nle-OH (25 mmol, 5 equiv) and then 16.22 g Fmoc-L-Arg- (Pbf) -OH, 9.33 g Fmoc-L-Phg-OH, 9.33 g Fmoc-D-Phg-OH or 8.84 g of Fmoc-L-Nle-OH (25 mmol; 5 equiv) were combined in sequence.

After preparation, the peptidyl resin was washed with DCM (5 × 3 min) and then dried by nitrogen flow.

Fmoc  General Removal of N-Terminal Protectors

The Fmoc N-terminal protecting group of the peptidyl resin obtained in Examples 1 and 2 was deprotected as described in the general method (20% piperidine, 1 × 5 min + 1 × 20 min). The peptidyl resin was washed with DMF (5 × 1 min), DCM (4 × 1 min), diethyl ether (4 × 1 min) and then dried under vacuum.

Example  Obtained in 3 Peptidyl  On resin R _One Palmitoyl group  How to introduce

2.56 g of palmitic acid (10 mmol; 10 equivalents) predissolved in DMF (1 mL) in the presence of 1.53 g of HOBt (10 mmol; 10 equivalents) and 1.54 mL of DIPCDI (10 mmol; 10 equivalents) To 1 mmol of peptidyl resin obtained from After reacting this mixture for 15 minutes, the resin was reacted with THF (5 × 1 min), DCM (5 × 1 min), DMF (5 × 1 min), MeOH (5 × 1 min), DMF (5 × 1 min). Washed with THF (5 × 1 min), DMF (5 × 1 min), DCM (4 × 1 min), ether (3 × 1 min) and dried under vacuum.

Example  Obtained in 3 Peptidyl  On resin Acetyl group R _One How to introduce

1 mmol of the peptidyl resin obtained in Example 3 was treated with 25 equivalents of acetic anhydride in the presence of 25 equivalents of DIEA using 5 mL of DMF as solvent. After reacting for 30 minutes, the peptidyl resin was washed with DMF (5 × 1 min), DCM (4 × 1 min), diethyl ether (4 × 1 min), and dried under vacuum.

Example  Obtained in 3, 4 and 5 Peptidyl  On resin Acetyl group R _One How to introduce

200 mg of dry peptidyl resin obtained in Examples 3, 4 and 5 were treated with 5 mL of TFA-TIS-H ₂ O (90: 5: 5) under stirring at room temperature for 2 hours. The filtrate was collected on 50 mL of cold diethyl ether, then filtered through a polypropylene syringe equipped with a disc of porous polyethylene and washed five times with 50 mL of diethyl ether. The final precipitate was dried under vacuum.

HPLC analysis of the peptide obtained in the gradient of MeCN (+ 0.07% TFA) in H ₂ O (+ 0.1% TFA) showed purity in excess of 80% in all cases. Confirmation of the obtained peptide was achieved by ES-MS.

Polymer  Support and R ₂  substitution Amines  Cutting method of derivatives with: Ac - X _n - AA _One - AA ₂ -AA ₃ -AA ₄ -Y _m -NH- (CH ₂ ) ₁₅ -CH ₃ Obtained in the above formula AA ₄ Is -L- Phg -, -D- Phg - or - Gly -ego; AA ₃ -L- Trp -, -L- Tyr -Or -L- Val -; AA ₂ Is -L- Ala -, -L- Cit -, -L-Nle-, -L- Phg -Or-D- Phg -ego; AA _One -L- Arg -, -L- Phg -, -D- Phg -Or -L- Nle -; n and m are zero.

₃ mL of 150 mg of the peptidyl resin Ac-X _n -AA ₁ -AA ₂ -AA ₃ -AA ₄ -Y _m -O-2-ClTrt-® of Example 5, pre-dried in vacuo in the presence of KOH in 3 mL in DCM By treatment with 3% solution of TFA, peptide Ac-X _n -AA ₁ -AA ₂ -AA ₃ -AA ₄ -Y _m -OH with a fully protected side chain was obtained. The filtrate was collected on 50 mL of cold diethyl ether and then repeated three times. The ethereal solution was evaporated to dryness in vacuo at room temperature and the precipitate dissolved in 50% MeCN in H ₂ O and then lyophilized. The 10 mg of crude product thus obtained was weighed in a flask, and 3 equivalents of hexadecylamine and 25 mL of anhydrous DMF were added thereto. Then, 2 equivalents of DIPCDI was added and reacted at 47 ° C. using magnetic stirring. The reaction was monitored by HPLC to confirm that the initial product disappeared. This phenomenon was completed after 24 to 48 hours. The solvent was dried twice and coevaporated using DCM. Thus obtained [residue with fully protected side chain Ac-X _n -AA ₁ -AA ₂ -AA ₃ -AA ₄ -Y _m -NH- (CH ₂ ) ₁₅ -CH ₃ ] was diluted to 25 mL of DCM-TFA- Resuspended in anisole (49: 49: 2) mixture and allowed to react at room temperature for 30 minutes. It was added on 250 mL cold diethyl ether, then the solvent was evaporated under reduced pressure and further co-evaporated twice with ether. This residue was dissolved in 50% MeCN mixture in H ₂ O and then lyophilized.

HPLC analysis of the peptide obtained in the gradient of MeCN (+ 0.07% TFA) in H ₂ O (+ 0.1% TFA) showed purity in excess of 70% in all cases. Confirmation of the obtained peptide was achieved by ES-MS.

Elastase Inhibition Assay

Peptides were resuspended in water in the presence of 0.5% DMSO. Assays were performed on black microplates with 96 wells using EnzChek ^® Elastase Assay Kit (Molecular Probes). To this end, the peptide is preincubated at 0.1 mM with 0.4 units / mL of elastase under moderate agitation for 1 hour at room temperature, after which the conjugated substrate is fluorescein at a final concentration of 25 μg / mL. (DQ ^™ Elastin) and the reaction was allowed to proceed for 2 hours at room temperature under stirring while protecting from light. Fluorescently inhibited substrates are degraded by elastase to produce fluorescent fragments, which were monitored by fluorescence using a FLUOstar Galaxy Reader (BMG Lab Technologies) using a 485 nm filter for excitation and a 530 nm filter for emission. .

Table 2 is a list of peptides showing that the inhibition rate exceeds 45%. Inhibition rates were normalized against the mean inhibition rate baseline.

 Elastase Inhibition Percent  Peptide control%  Ac-Phg-Phg-L-Val-Phg-OH 76.1  Ac-Phg-Phg-L-Val-Gly-OH 64.2  Ac-Phg-Phg-L-Trp-Phg-OH 84.2  Ac-Phg-Phg-L-Trp-Gly-OH 65.0  Ac-L-Nle-Phg-L-Val-Phg-OH 73.8  Ac-L-Nle-Phg-L-Val-Gly-OH 62.7  Ac-L-Nle-Phg-L-Trp-Phg-OH 90.0  Ac-L-Nle-Phg-L-Trp-Gly-OH 69.6  Ac-L-Arg-Phg-L-Val-Phg-OH 82.3  Ac-L-Arg-Phg-L-Val-Gly-OH 81.4  Ac-L-Arg-Phg-L-Trp-Phg-OH 90.3  Ac-L-Arg-Phg-L-Trp-Gly-OH 66.9 Palm-L-Arg-Phg-L-Trp-Phg-NH ₂ 57.1 Ac-L-Arg-Phg-L-Trp-Phg-NH- (CH ₂ ) ₁₅ -CH ₃ 53.7  Ac-Phg-L-Trp-Phg-OH 45.1

Human Elastase Inhibition Assay

Human neutrophil elastase was reconstituted at 5 μg / mL in 50 mM sodium acetate, 200 mm NaCl, pH 5.5 buffer. 0.2 μg / mL protease was preincubated with the peptide at a final concentration of 0.05-2 mM in a black microplate with 96 wells for 1 hour at room temperature. After preculture, 25 μg / mL of substrate (MeOSuc-Ala-Ala-Pro-Val aminomethyl comarin) was added to the wells and the samples were incubated for 2 hours at room temperature while protecting from light. The fluorescence produced by the degradation of the substrate was measured using an automated multiplate fluorescens reader that was excited at 370 nm and read at 460 nm.

The results were corrected from the fluorescence numerical baseline in the absence of elastase and product and normalized to the fluorescence of the control, and the minimum inhibitory concentration for each peptide was determined. Table 3 shows the best inhibitory values obtained for the peptides.

Minimum inhibitory concentration of peptides against human elastase  Peptide IC50 (mM)  H-L-Arg-Phg-Val-Phg-OH 0.094  H-L-Arg-Phg-Val-Gly-OH 0.407  H-L-Arg-Phg-Trp-Phg-OH 0.103

Palm -L- Nle - Phg -L- Tyr - Phg - NH ₂ Containing Cosmetics  Preparation of the composition

Ac -L- Arg - Phg -L- Val - Phg - NH ₂ Preparation of Liposomes Containing

Dipalmitoylphosphatidylcholine (DPPC) was weighed and dissolved in chloroform. The solvent was evaporated under vacuum until a thin layer of phospholipid was obtained, followed by hydration of the thin layer by treatment with an aqueous peptide solution (containing Phenonip®) at a predetermined concentration at 55 ° C. to obtain an MLV liposome. ULV liposomes were obtained by immersing the MLV liposomes in an ultrasonic bath for eight cycles of two minutes at 55 ° C. at five minute intervals. The size of ULV liposomes was reduced by passing through an extrusion system at high pressure.

Ac - Phg - Phg -L- Trp - Phg - OH Containing Facial  Composition of cream

Ac -L- Arg - Phg -L- Val - Phg - OH Preparation of the composition in the form of liposome gel containing

The liposomes of Example 11 were dispersed in water with preservatives (EDTA, imidazolidinyl urea and Phenonip ^® ) under gentle stirring. Hispagel ^® 200 [INCI: water, glycerin, glyceryl polyacrylate] was added and stirred gently until a homogeneous mixture was obtained.

Ac -L- Arg - Phg -L- Trp - Phg - OH Containing Of microemulsion  Furtherance

Ac -L- Arg - Phg -L- Trp - Phg - OH Containing Body gel  Furtherance

Ac -L- Arg - Phg -L- Trp - Phg - NH -( CH ₂ ) ₁₅ - CH ₃ Containing Hair lotion  Furtherance

Ac -L- Arg - Phg -L- Trp - Phg - OH Mixed Michelle  Preparation of the composition

The ingredients of phase A were weighed in a container suitable for the complete sample and gently warmed to about 30 ° C. to help dissolve some preservatives. The components of phase B were then added and homogenized under moderate agitation.

The ingredients of phase C were then added with continued stirring, followed by the slow stirring to avoid foaming.

pH was adjusted to 5.5 ~ 6.5.

Example  Effect on increasing skin elasticity of the composition of 15

To evaluate the effectiveness of the composition of Example 15 of the present invention, the lotion was applied to the thighs of 20 volunteers twice daily for two months.

Skin elasticity was measured using a cutometer and the results are shown in Table 4.

 Measurement of skin elasticity Measurement of maximum strain (R ₀ ) T ₀ T _f Average change change% t value 0.256 0.216 -0.04 -15.6% p <0.001 Measurement of Elasticity (R ₂ ) T ₀ Tf Average change change% t value 0.572 0.652 0.08 14.0% p <0.001

An average 14% increase in elasticity was achieved.

Example  Corresponding to the composition of 15 Placebo  Effect on increasing skin elasticity of the composition

To assess the effect of the placebo composition (peptide Ac-L-Arg-Phg-L-Trp-Phg-OH free) corresponding to the composition of Example 15, a panel of 20 volunteers performed this lotion on 1 day for 2 months. Twice was applied to the thighs.

Skin elasticity was measured using a cutometer and the results are shown in Table 5.

 Measurement of skin elasticity Measurement of maximum strain (R ₀ ) T ₀ T _f Average change change% t value 0.243 0.234 -0.009 -3.7% p> 0.05 Measurement of Elasticity (R ₂ ) T ₀ T _f Average change change% t value 0.584 0.567 -0.017 -2.9% p> 0.05

No increase in skin elasticity was observed after 2 months of treatment.

Collagen Synthesis Promotion Analysis

Human dermal fibroblasts were grown until confluence was achieved in MI06 medium supplemented with specific growth factors for fibroblasts. These cells were then trypsinized and then planted in 24-well plates at a level of 5 × 10 ⁴ cells / well. After 24 hours incubation at 37 ° C. under 5% CO ₂ atmosphere, fresh medium was added with a scalar dilution of 15 μg / mL of the peptide or with the carrier as a negative control. The cells were further incubated for 48 hours before the medium was collected.

Analysis of the amount of type I collagen secreted was performed by ELISA assay. In brief, the previously collected medium was coated on a 24-well plate at 50 μl per well and allowed to adsorb overnight at 4 ° C. under a humid atmosphere. This plate was then washed three times with PBS (+ 0.05% Tween 20) and then blocked with 3% BSA for 1 hour. After blocking, the plates were treated with anti-type collagen antibody (1: 1000 in PBS, 0.05% Tween 20, 1% BSA) for 2 hours. After this culture, a secondary antibody (goat anti-mouse IgG-HRP antibody, Molecular Probes, 1: 1000 in PBS, 0.05% Tween 20, 1% BSA) was added. After incubating this plate with phosphatase substrate for 30 minutes, the reaction was stopped by adding 3M H ₂ SO ₄ . Absorbance at 490 nm was recorded using a microplate reader and collagen concentration was determined using a standard linear regression curve for type I collagen. Values were normalized to collagen levels in negative control experiments, yielding an increase in type I collagen for all treatments. Table 6 lists the calculated rate of increase in the type I collagen content.

 Increase in type I collagen by peptide treatment  Peptide Increase  Control group 0%  H-L-Arg-Phg-L-Val-Phg-OH 18%  H-L-Arg-Phg-L-Val-Gly-OH 16%  H-L-Arg-Phg-L-Trp-Phg-OH 99%

Claims (50)

A peptide of Formula 1,
[Formula 1]
R ₁ -W _p -X _n -AA ₁ -AA ₂ -AA ₃ -AA ₄ -Y _m -R ₂
As stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, at least one of the amino acids AA ₁ , AA ₂ and AA ₄ is a non-coding amino acid,
AA ₁ is selected from the group consisting of -Arg-, -Phg- and -Nle- or is one bond,
AA ₂ is selected from the group consisting of -Ala-, -Phg-, -Cit- and -Nle-,
AA ₃ is selected from the group consisting of -Trp-, -Val- and -Tyr-,
AA ₄ is selected from the group consisting of -Phg- and -Gly-;
W, X and Y are independently selected from the group consisting of coding or non-coding amino acids,
p, n and m are 0 to 1,
R ₁ is H, substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted Or unsubstituted aralkyl and R ₅ -CO-,
R ₂ is selected from the group consisting of -NR ₃ R ₄ , -OR ₃ and -SR ₃ ,
Wherein R ₃ and R ₄ are H, substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Independently selected from the group consisting of substituted aryl, and substituted or unsubstituted aralkyl,
R ₅ is H, a substituted or unsubstituted acyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, and substituted Or an unsubstituted heteroarylalkyl,
If AA ₁ is one bond, AA ₂ is -Phg- and AA ₃ is -Trp-. The method of claim 1,
R ₁ is selected from the group consisting of H and R ₅ -CO-, R ₅ is substituted or unsubstituted C ₁ -C ₂₄ alkyl, substituted or unsubstituted C ₂ -C ₂₄ alkenyl, substituted or unsubstituted Substituted C ₂ -C ₂₄ alkynyl, substituted or unsubstituted C ₃ -C ₂₄ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkynyl , Substituted or unsubstituted C ₆ -C ₃₀ aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, substituted or unsubstituted heterocyclyl having 3 to 10 ring members, and 2 Peptides, characterized in that selected from the group consisting of substituted or unsubstituted heteroarylalkyl containing an alkyl chain having 1 to 3 carbon atoms and 1 to 3 non-carbon atoms and 1 to 6 carbon atoms. The method of claim 2,
R ₁ is H, acetyl, tert -butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and Peptides, characterized in that selected from linoleyl group. 4. The method according to any one of claims 1 to 3,
R ₂ is —NR ₃ R ₄ or —OR ₃ , wherein R ₃ and R ₄ are H, substituted or unsubstituted C ₁ -C ₂₄ alkyl, substituted or unsubstituted C ₂ -C ₂₄ alkenyl, substituted Or unsubstituted C ₂ -C ₂₄ alkynyl, substituted or unsubstituted C ₃ -C ₂₄ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, substituted or unsubstituted C ₅ -C ₂₄ cyclo Alkynyl, substituted or unsubstituted C ₆ -C ₃₀ aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, substituted or unsubstituted heterocyclyl having 3 to 10 ring members, and 2 to A peptide characterized in that it is independently selected from the group consisting of substituted or unsubstituted heteroarylalkyl containing 24 carbon atoms and 1 to 3 non-carbon atoms and having 1 to 6 carbon atoms. The method of claim 4, wherein
And R ₃ and R ₄ are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. 6. The method according to any one of claims 1 to 5,
AA ₂ and AA ₄ is a peptide, characterized in that Phg. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl and palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Tyr-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, Peptide, characterized in that it is independently selected from ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Nle-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Tyr-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, Peptide, characterized in that it is independently selected from ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, Peptide, characterized in that it is independently selected from ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Nle-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, Peptide, characterized in that it is independently selected from ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Val-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, Peptide, characterized in that it is independently selected from ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Phg- or -D-Phg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , the R ₃ and R ₄ is a peptide characterized in that it is independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 6,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is one bond, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Trp-, AA ₄ is -L-Phg- or -D-Phg-, R ₂ is -NR ₃ R ₄ or -OR ₃ , and R ₃ and R ₄ are H, methyl, ethyl , Hexyl, dodecyl and hexadecyl. The method according to any one of claims 1 to 5,
R ₁ is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl group, AA ₁ is -L-Arg-, AA ₂ is -L-Phg- or -D-Phg-, AA ₃ is -L-Val-, AA ₄ is -Gly-, R ₂ is -NR ₃ R ₄ or -OR ₃ , wherein R ₃ and R ₄ are H, methyl, ethyl, hexyl, dodecyl and hexa Peptide, characterized in that independently selected from decyl. The method according to any one of claims 1 to 14,
R ₁ is selected from the group consisting of H, acetyl and palmitoyl, and R ₂ is selected from the group consisting of -OH and -NH ₂ . The method according to any one of the preceding claims,
Wherein p, n and m are zero. 17. A peptide of formula 1 according to any one of claims 1 to 16, stereoisomers thereof, mixtures thereof and / or cosmetics or pharmaceuticals for use in the treatment and / or care of skin, mucous membranes and / or scalp. Acceptable salts. The method of claim 17,
Peptides used in the treatment, prevention and / or management of diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp resulting from elastase activity. The method of claim 17,
Peptides used in the treatment, prevention and / or management of diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp by providing an advantage of promoting collagen synthesis. The method of claim 18,
Peptides characterized in that elastase activity occurs in the skin, mucous membranes and / or scalp. 21. The method according to any one of claims 17 to 20,
Said treatment, prevention and / or management is by topical or transdermal application of said peptide. The method of claim 21,
The topical or transdermal application may be by syringeless pressure injection, microelectric patch or combinations thereof, such as iontophoresis, ultrasonography, electroporation, mechanical pressure, osmotic pressure gradient, closure therapy, microinjection or oxygen injection. Peptides characterized in that carried out. 21. The method according to any one of claims 17 to 20,
Said treatment, prevention and / or management is by oral administration of said peptide. The method according to any one of claims 17 to 18,
Wherein said treatment, prevention and / or care increases skin elasticity. 20. The method according to any one of claims 17 to 19,
Said treatment, prophylaxis and / or management reduce or eliminate facial wrinkles. The method according to any one of claims 17 to 23,
The diseases, disorders and / or diseases of the skin, mucous membranes and / or scalp may include wrinkles, impression wrinkles, stretch marks, skin aging, skin photoaging, wound recovery disorders, ulcers, diabetic ulcers, keloids, Thickening scars, acne, cellulite, orange peel skin, elastic tissue atrophy, elastic fibrosis, keratosis, inflammation, dermatitis, atopic dermatitis, allergic contact dermatitis, sensitive skin, eczema, blistering dermatitis, gingivitis, periodontitis, skin cancer, Peptides selected from the group consisting of tumor infiltration, tumor metastasis, capillary dilemma, couperosis, lower extremity varicose veins, dark circles around the eyes, drooping eyes, hair loss and hair damage, injections and / or psoriasis . The method of claim 17,
Wherein said treatment, prevention and / or management reduces, delays and / or prevents signs of aging and / or photoaging. The method of claim 17,
Peptide, characterized in that used for hair treatment or hair hygiene. The method of claim 17,
Peptides characterized in that they are used for the treatment and / or care of body skin or for body hygiene. A process for the preparation of a peptide of formula (1) according to any one of claims 1 to 16, stereoisomers thereof, mixtures thereof and / or cosmetic or pharmaceutically acceptable salts, the process comprising: solid or solution phase Characterized in that it is carried out. 31. The method of claim 30,
The protecting group of the free amino group is selected from the group consisting of Boc, Fmoc, Trt, Troc, Teoc, Alloc, Mtt, Z, ClZ, Dnp, Dde, ivDde and Adpoc, and the protecting group of the free carboxyl group is tBu, Bzl, cHex, All Is selected from the group consisting of esters of Dmab, 2-phenylisopropyl, Fm and Trt, the arginine side chain is protected with a protecting group selected from the group consisting of Alloc, Tos, Pmc, Pbf, nitro and Mtr, and the tryptophan side chain is And a protecting group selected from the group consisting of Boc and Mts, wherein the tyrosine side chain is protected with a protecting group selected from the group consisting of 2-BrZ, tBu, All, Bzl and 2,6-diClZ. A cosmetic or pharmaceutically effective amount of at least one peptide of formula 1 according to any one of claims 1 to 16, stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts thereof. A cosmetic or pharmaceutical composition comprising at least one excipient or cosmetic or a pharmaceutically acceptable adjuvant. 33. The method of claim 32,
The peptide of Formula 1 is a composition, characterized in that the concentration of 0.000001% to 20% by weight relative to the total weight of the composition. The method of claim 33, wherein
The peptide of Formula 1 is a composition, characterized in that the concentration of 0.0001% to 5% by weight relative to the total weight of the composition. The method according to any one of claims 32 to 34, wherein
The peptide of Formula 1, its stereoisomers, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts thereof are liposomes, mixed liposomes, oleosomes, niosomes, millicapsules, microcapsules, nanocapsules, sponges, Cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant-phospholipid mixed micelles, millispeare, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, miniparticles, milliparticles, microparticles, A composition characterized in that it is incorporated into a cosmetic or pharmaceutically acceptable delivery system selected from the group consisting of nanoparticles and solid lipid nanoparticles. 36. The method of claim 35 wherein
Wherein said microemulsion is a water in oil microemulsion having an internal structure of reverse micelles. The method according to any one of claims 32 to 36,
The peptide of Formula 1, its stereoisomers, mixtures thereof and / or cosmetics or pharmaceutically acceptable salts are cosmetic or pharmaceutically acceptable selected from the group consisting of talc, bentonite, silica, starch or maltodextrin. A composition characterized by adsorbing onto an acceptable solid organic polymer or solid inorganic substrate. The method according to any one of claims 32 to 37,
The compositions are creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels, water alcohol solutions, hydroglycol solutions, hydrogels, application potions, ceras, soaps, shampoos, Conditioner, serum, ointment, mousse, pomade, powder, bar, pencil, spray, aerosol, capsule, gelatin capsule, tablet, dragee, powder, granule, chewing gum, solution, suspension, emulsion, syrup, polysaccharide film, jelly and gelatin A composition, characterized in that the composition selected from the group consisting of. The method according to any one of claims 32 to 38,
Wherein said composition is a product selected from the group consisting of concealer, makeup foundation, makeup removal lotion, makeup removal milk, eye shadow, lipstick, lip gloss, lip protector and powder. The method according to any one of claims 32 to 38,
The peptide of formula 1, stereoisomers thereof, mixtures thereof and / or cosmetically or pharmaceutically acceptable salts thereof are incorporated into fabrics, nonwovens or medical means. The method of claim 40, wherein
The fabric, nonwoven or medical means may be bandages, gauze, shirts, stockings, socks, underwear, girdle, gloves, diapers, sanitary napkins, dressings, bed spreads, handkerchiefs, hydrogels, tacky patches, non-stick patches, microelectric patches and face Composition selected from the group consisting of masks. The method according to any one of claims 32 to 41,
The composition comprises an elastase inhibitor, a substrate metalloproteinase inhibitor, a melanin synthesis promoter or inhibitor, a whitening or bleaching agent, a proigmenting agent, a self-tanning agent, an anti-aging agent, a NO-synthetic inhibitor, 5 -α-reductase inhibitors, lysyl- and / or propyl-hydroxylase inhibitors, antioxidants, free radical scavengers and / or air pollution inhibitors, reactive carbonyl species scavenger, anti-glycosylation agents, antihistamines, antiemetics, antiviral agents , Repellents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners, humectants, moisture retaining substances, alpha hydroxy acids, beta hydroxy acids, humectants, epithelial hydrolases, vitamins, pigments or coloring agents, Dyes, gelling polymers, thickeners, surfactants, emollients, anti-wrinkle agents, anti-eye sagging or therapeutic agents, exfoliants, antibacterial agents, antifungal agents, mold growth inhibitors, Fungicides, bacteriostatic agents, substances capable of promoting the synthesis of and / or inhibiting the synthesis of dermal or epidermal polymers, and / or inhibiting the degradation of their molecules, collagen synthesis promoters, elastin synthesis promoters, decorin synthesis promoters, laminin synthesis promoters, defesin Synthesis promoters, chaperone synthesis promoters, aquaporin synthesis promoters, hyaluronic acid synthesis promoters, fibronectin synthesis promoters, sirtuins synthesis promoters, lipid and keratin component synthesis promoters, ceramide synthesis promoters, collagen degradation inhibitors, other elastin degradation inhibitors , Serine protease inhibitors such as cathepsin G, keratinocyte proliferation promoter, adiocyte proliferation promoter, melanocyte proliferation promoter, keratinocyte differentiation promoter, adiposite differentiation promoter, acetylcholinesterase inhibitor , Skin relaxant, glycosaminoglycan synthesis promoter, excess Antioxidant, Comedolytic Agent, Anti-Psoriasis, DNA Repair, DNA Protector, Stabilizer, Anti-itch, Sensitive Skin Treatment and / or Care Agent, Hardener, Stretch Mark Preventer, Binder, Sebum Production Regulator, Fat Powder Release or lipolytic accelerators, anti-cellulite, antiperspirants, recovery accelerators, recovery co-adjuvant, re-epithelialization co-adjuvant, re-epithelialization co-adjuvant, cytokine growth factor, sedative, anti-inflammatory, anesthetic, capillary circulatory system and / or micro Circulatory agents, angiogenesis promoters, vascular permeability inhibitors, anti-edema agents, cell metabolism agents, dermal-epidermal binding enhancers, hair growth inducers, hair growth inhibitors or retarders, preservatives, fragrances, chelating agents, vegetable extracts, essential oils , Seaweed extracts, substances obtained in the process of biofermentation, natural salts, cell extracts and sunscreen, ultraviolet A and And / or a cosmetically or pharmaceutically effective amount of at least one adjuvant, selected from the group consisting of organic or mineral photoprotectants against B or mixtures thereof. 43. The method of claim 42,
Wherein said active agent is synthetically derived or is a plant extract or is obtained by a biofermentation process. The method of claim 42 or 43,
Wherein said adjuvant is selected from the group consisting of reactive carbonyl species scavenger, free group trapping agent and / or anti-glycosylating agent. 45. The method of claim 44,
Wherein said reactive carbonyl species scavenger, free group trapping agent and / or anti-glycosylating agent is selected from the group consisting of tripeptide-1 and diaminopropionyl tripeptide-33. The method of claim 42 or 43,
Wherein said adjuvant is selected from the group consisting of anti-wrinkle and / or anti-aging agents. The method of claim 46,
The anti-wrinkle and / or anti-ageing agent may be pentapeptide-18, acetyl hexapeptide-8, acetyl heptapeptide-4, acetyl octapeptide-3, acetyl tetrapeptide-5, acetyl tripeptide-30 citrulline, dimethylmethoxy chromanol , Dimethylmethoxy chromatin palmitate, diaminopropinoyl tripeptide-33, Pseudoaltermonas fermented extract, Pseudoaltermonas fermented extract and hydrolyzed wheat protein, hydrolyzed soy protein and tripeptide-10 A mixture of citrulline and tripeptide-1, a mixture of hydrolyzed wheat protein and hydrolyzed soy protein and tripeptide-1. The method of claim 46,
The anti-wrinkle and / or anti-aging agent is from the group consisting of tripeptide-10 citrulline, acetyl hesapeptide-30, lysine HCl and lecithin and tripeptide-10 citrulline, lysine HCl and lecithin and tripeptide-9 citrulline Selected composition. The method of claim 42 or 43,
Said adjuvant is selected from the group consisting of anti-cellulite, lipolytic and / or anti-edema agents. The method of claim 42 or 43,
Wherein said anti-cellulite, lipolytic and / or anti-edema agent is selected from the group consisting of caffeine, escin and carnitine.